Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2020 Dec 1.
Published in final edited form as: Prog Neurobiol. 2019 Sep 21;183:101697. doi: 10.1016/j.pneurobio.2019.101697

Repeat-associated non-AUG (RAN) translation mechanisms running into focus for GGGGCC-repeat associated ALS/FTD.

Lindsey D Goodman 1, Nancy M Bonini 1,2,*
PMCID: PMC6941355  NIHMSID: NIHMS1545266  PMID: 31550516

Abstract

Many human diseases are associated with the expansion of repeat sequences within the genes. It has become clear that expressed disease transcripts bearing such long repeats can undergo translation, even in the absence of a canonical AUG start codon. Termed “RAN translation” for repeat associated non-AUG translation, this process is becoming increasingly prominent as a contributor to these disorders. Here we discuss mechanisms and variables that impact translation of the repeat sequences associated with the C9orf72 gene. Expansions of a G4C2 repeat within intron 1 of this gene are associated with the motor neuron disease ALS and dementia FTD, which comprise a clinical and pathological spectrum. RAN translation of G4C2 repeat expansions have been studied in vitro, in cells in culture and in the fly in vivo. Cellular states that lead to RAN translation, like stress, may be critical contributors to disease progression. Greater elucidation of the mechanisms that impact this process and the translation and other factors contributing, will lead to greater understanding of the repeat expansion diseases, to the potential development of novel approaches to therapeutics, and to a greater understanding of how these players impact biological processes in the absence of disease.

1. INTRODUCTION

Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease primarily affecting upper and lower motor neurons within the motor cortex, brain stem and spinal cord (Al-Chalabi and Hardiman, 2013; Logroscino and Piccininni, 2019). The loss of these neurons causes weakness, spasticity, paralysis, and death, usually within 2-5 years of onset. ALS is the most common motor-neuron disease, affecting ~2-5 in 100,000 individuals (annually). In recent years, it has become evident that ALS exists as a spectrum disorder with frontotemporal degeneration (FTD) as these diseases share clinical and pathological features (A.-L. Ji et al., 2017). FTD is the third most common neurodegenerative disease primarily affecting frontal and temporal cortical neurons, leading to memory loss and additional symptoms (Pottier et al., 2016; Raffaele et al., 2019; Seltman and Matthews, 2012; Sieben et al., 2012). FTD affects ~3-15 in 100,000 individuals (annually), while the risk for FTD is higher among individuals 45-64 years old (Knopman and Roberts, 2011; Pottier et al., 2016). The average lifespan for FTD patients varies between ~5 and ~10 years after disease onset. ALS and FTD represent two extremes of one spectrum disorder, and clinical presentation in patients can fall between these two diagnoses, resulting in both motor and cognitive deficits and a diagnosis of ALS/FTD. Interestingly, different families carrying the same disease-associated mutation or individuals from the same afflicted family can present with ALS only, FTD only, or ALS/FTD symptoms, potentially the result of environmental and genetic modifiers (Renton et al., 2011; van Blitterswijk et al., 2014a, 2014b). Despite a surge in investigations on ALS/FTD, successful therapeutics have yet to be developed, supporting that a greater understanding of disease mechanisms is needed.

While there are multiple mutations associated with ALS/FTD, a common theme is that there are disruptions in RNA-based pathways (Ito et al., 2017; A.-L. Ji et al., 2017; Zhao et al., 2018). In particular, TDP-43, an RNA-binding protein encoded by the TARDBP gene, is the primary component of ubiquitinated inclusions in ALS and a subset of FTD (Neumann et al., 2006; Prasad et al., 2019). Further, a mutation of a GGGGCC hexanucleotide repeat expansion within C9orf72 has been identified as the most common mutation known to date. Termed G4C2, this mutation is associated with disease when >30 repeats are found within the first intron of C9orf72, located on chromosome 9p21 (DeJesus-Hernandez et al., 2011; Renton et al., 2011). The maximum number of repeats is estimated to be in the thousands (Buchman et al., 2013; Dobson-Stone et al., 2013; Hübers et al., 2014; van Blitterswijk et al., 2013). The percentage of reported familial ALS/FTD patients harboring this mutation varies between ~25% and ~60%, with a higher frequency seen in European populations (DeJesus-Hernandez et al., 2011; Gijselinck et al., 2012; Renton et al., 2011; van Blitterswijk et al., 2012). Non-familial ALS/FTD, termed sporadic ALS/FTD, can also present with this mutation at a ~5-10% frequency. Recently, a number of studies have shown that TDP-43 inclusion formation and the aberrant expression of the hexanucleotide repeat expansions in the C9orf72 gene are related (Cooper-Knock et al., 2015a; Davidson et al., 2014; Edbauer and Haass, 2016; Saberi et al., 2018). Patients bearing the G4C2-mutation have TDP-43 pathology, with accumulating evidence indicating that these two features are connected (Chew et al., 2019, 2015; Cooper-Knock et al., 2015b; Solomon et al., 2018; Vatsavayai et al., 2016). Importantly, TDP-43 pathology may be induced by the expression of the hexanucleotide repeat, while the underlying mechanism needs further elucidation (Chew et al., 2015, 2019; Solomon et al., 2018).

Currently, there are three leading hypotheses as to how G4C2 confers toxicity: a loss-of-function hypothesis centered around the reduced expression of the C9orf72 protein and two related gain-of-function hypotheses centered around the aberrant expression of the G4C2-containing intron. Pertinent to gain-of-function mechanisms, in patient tissue both sense-G4C2 and antisense-G2C4 RNA foci are found (Cooper-Knock et al., 2015b; DeJesus-Hernandez et al., 2011; Gendron et al., 2013; Lagier-Tourenne et al., 2013; Mizielinska et al., 2013), demonstrating that bidirectional transcription occurs at C9orf72 to produce 2 potentially toxic RNA species. Further, these RNAs can undergo repeat-associate non-AUG (RAN) translation to produce 5 potentially toxic dipeptides: GA. GR, GP, PA, and PR (Gendron et al., 2013; Mackenzie et al., 2013; Mann et al., 2013; Mori et al., 2013a, 2013b; Zu et al., 2013). RAN-translation has been reported to occur in multiple repeat-expansion associated diseases (Nguyen et al., 2019; Zu et al., 2018). Notably, the resulting dipeptides can form aggregates in patients and are associated with toxicity in model systems (Balendra and Isaacs, 2018; Cook and Petrucelli, 2019). Here we will focus on pertinent information to translation of these repeats; broader reviews of disease mechanisms can be found elsewhere (Balendra and Isaacs, 2018; Cook and Petrucelli, 2019; Yuva-Aydemir et al., 2018).

The G4C2 mutation is one in a growing list of repeat-expansion diseases associated with neurodegeneration (Nguyen et al., 2019; Todd and Paulson, 2010). A well studied repeat is a CAG-expansion of >35 repeats found in polyglutamine diseases, such as Huntington’s disease (HD) and the spinocerebellar ataxias (SCA1, 2, 3, 6, 7, 8, 17). Another repeat-expansion that will be discussed herein is the CGG-expansion of >55 repeats that is associated with Fragile-X-associated tremor and ataxia syndrome (FXTAS). Overall, a common theme among these disorders is that expression of the repeat-RNA, independent of the genetic context in which they occur in patients, can cause toxic effects in model systems. Importantly, these RNAs can undergo translation in the absence of a canonical AUG start codon, to produce aggregate-prone peptides that are thought to contribute to toxicity. We discuss current literature on RAN-translation from these repeat-containing RNAs, while attempting to reconcile conflicting data for the G4C2 repeat of C9orf72-ALS/FTD.

2. PATHOLOGICAL FEATURES OF C9ORF72-ALS/FTD

In order to understand the impact of RAN-translation in disease, one must first understand pathological data in C9orf72-associated ALS/FTD. Importantly, despite extreme toxicity associated with expression of specific dipeptides in model systems, pathological data is currently in conflict with the idea that these dipeptides are driving toxicity. Readers are referred to a recent detailed review of clinical pathology (Vatsavayai et al., 2019); we highlight key points.

The G4C2 expansion within the C9orf72 gene is located between non-coding exons, 1a and 1b, placing it within the first intron of mRNA variants 1 and 3 and within the promotor of variant 2 (Fig. 1A–B). C9orf72 encodes a differentially expressed in neoplastic versus normal cells (DENN) protein which plays a role in endosomal and autophagy pathways (Chitiprolu et al., 2018; Farg et al., 2014; Frick et al. 2018; Ho et al., 2019; Levine et al., 2013; Sellier et al., 2016; Shi et al., 2018; Webster et al., 2016; Zhang et al., 2012). All mRNA variants are downregulated in C9+ tissue, with variant 2 showing the strongest decrease in expression (van Blitterswijk et al., 2015). Further, expression of the protein isoform, C9orf72-Long, is reduced in C9+ tissue, while it may be the more abundant isoform (Frick et al., 2018; Saberi et al., 2018; Waite et al., 2014; Xiao et al., 2015). Potential disease mechanisms associated with C9orf72 haploinsufficiency are a focus of current investigations. However, the extent to which C9orf72 downregulation contributes to disease is unclear. Mouse models with disrupted murine C9orf72 expression do not show effects of neurodegeneration, but rather autoimmune defects (Atanasio et al., 2016; Y. J. Ji et al., 2017; Koppers et al., 2015; Lagier-Tourenne et al., 2013; O’Rourke et al., 2016; Sudria-Lopez et al., 2016). In contrast, zebrafish and C. elegans models lacking endogenous C9orf72 orthologues develop motor dysfunction (Ciura et al., 2013; Therrien et al., 2013), potentially the result of deficits during development (Ho et al., 2019; Yeh et al., 2018). Importantly, in C9+ patients, an upstream CpG island is methylated, shutting down the C9orf72 gene and effectively the aberrant expression of the G4C2-RNA (Belzil et al., 2014; Liu et al., 2014; McMillan et al., 2015; Russ et al., 2015; Xi et al., 2014, 2013). This mechanism is believed to be neuroprotective as increased methylation reduces RNA foci formation, dipeptide aggregation and neuron loss in patient brains. Notably, if the C9orf72 gene product was essential for maintaining neuron health, this methylation would be an unexpected response to the G4C2-mutation, as it would also decrease C9orf72-function. That said, a recent study suggested that depleted C9orf72 protein may play a synergistic role with dipeptide-associated toxicity in disease (Shi et al., 2018).

Figure 1: The impact of the repeat expansion within the C9orf72 gene.

Figure 1:

Open in a new tab

A. The C9orf72 gene is composed of 11 exons (grey boxes) with intron 1 located between exons 1A and 1B. Under normal conditions, three mRNA variants are produced after introns are spliced out (blue arrow). Variants 1 and 3 use a promoter region 5′ of exon 1A. Variant 2 uses a promoter region within intron 1. From these three mRNA variants, two C9orf72 protein isoforms (green) are translated: C9orf72-Short from mRNA variant 1 and C9orf72-Long from mRNA variants 2 and 3. B. A mutation of a (G4C2)n-repeat expansion (red) is located within intron 1 of C9orf72 in a subset of ALS/FTD cases. This expanded repeat disrupts both RNA and protein production from the C9orf72 gene. Importantly, multiple G4C2-containing RNA products could exist in patients, each carrying the G4C2-expansion in different contexts: a spliced intron bearing the repeat; aborted transcripts; and transcripts with the retained intron. Only RNA produced based on the “retained intron” hypothesis would be predicted to include a 5′ m7G-cap and a 3′ polyadenylated tail. C. Repeat-associated non-AUG (RAN-) translation occurs in C9+ ALS/FTD, producing 5 dipeptide products from the sense-G4C2 and antisense-G2C4 repeat RNA. The reading frame determines which dipeptide is produced while frameshifting could occur to produce multiple dipeptides from a single translation initiation. All five dipeptides can form insoluble aggregates in diseased tissue. In model systems, GR and PR are particularly toxic while toxic effects have also been seen with GA expression in mammalian systems (Balendra and Isaacs, 2018; Cook and Petrucelli, 2019; Freibaum and Taylor, 2017).

Under normal conditions, intron 1 of C9orf72 is spliced out of nascent C9orf72 transcripts and immediately degraded. Evidence suggests that the presence of the repeat expansion disrupts this process through unknown mechanisms and a stable G4C2-RNA remains present. Notably, this RNA could exist in a number of forms in patients, including: intronic RNA, C9orf72-mRNA transcripts retaining the intron (Niblock et al., 2016), and aborted C9orf72-RNA transcripts (Haeusler et al., 2014; van Blitterswijk et al., 2015) (Fig. 1B). Both sense-G4C2 and antisense-G2C4 RNA foci form throughout the nervous system, and are predominantly nuclear (DeJesus-Hernandez et al., 2011; Renton et al., 2011; Zu et al., 2013). Foci formation is not specific to neurons as they have been reported in glia and non-neuronal cells, albeit at lower relative frequencies (Gendron et al., 2013; Lagier-Tourenne et al., 2013; Mizielinska et al., 2013; Zu et al., 2013). Investigations into RNA-binding proteins that interact with G4C2-RNA have revealed a number of candidates, some of which co-localize with RNA foci in patients, including: ADARB2, SRSFs (1 and 2), ALYREF, hnRNPs (A1, A3, H, and K), Pur-α, nucleolin (Česnik et al., 2019; Haeusler et al., 2014; Kumar et al., 2017).

G4C2ǁG2C4 RNA can undergo RAN-translation through currently undefined mechanisms (discussed in section 3), producing five dipeptides (DPR): GA, GR, GP, PA, PR (Fig. 1C) (Ash et al., 2013; Gendron et al., 2013; Mori et al., 2013b, 2013a). These DPRs form aggregates in patient neurons but rarely in glia (Vatsavayai et al., 2019). In patients, DPR aggregates stain positive for p62 (an autophagic marker), predominantly stain negative for TDP-43, and are more frequent in the cytoplasm (Mann et al., 2013; Saberi et al., 2018). Rare, diffuse DPR staining has also been reported in patient neurons (Gendron et al., 2013; Mackenzie et al., 2015; Saberi et al., 2018; Schludi et al., 2015), arguing that associations with disease do not require visible aggregation. Further, soluble GP can be found in patient cerebral spinal fluid (CSF) and blood (Gendron et al., 2017; Lehmer et al., 2017).

Overall, sense-strand associated aggregates – GA, GR, and GPS – are more abundant than antisense-strand associated aggregates – PA, PR, GPAS. Of these, GA aggregates are most prominent (Mackenzie et al., 2015; Schludi et al., 2015). Currently, GPS and GPAS produced from the separate RNA stands are considered similar, while translation of GPS extends beyond the repeat to produce a unique C-terminal fragment that is not present in GPAS (Mori et al., 2013a; Zu et al., 2013). This fragment could alter stability or toxicity associated with GPS versus GPAS. Unique C-terminal fragments are also found in the other reading frames for GA, GR, PA, and PR.

Investigations into DPR-associated toxicity in model systems have revealed that expression of specific DPRs (expressed from non-G4C2 transcripts) may contribute to disease: GA, GR, and PR have been associated with toxicity in multiple model systems while GR and PR cause consistent, strong degenerative effects across systems (Balendra and Isaacs, 2018; Cook and Petrucelli, 2019; Yuva-Aydemir et al., 2018). In patients, targeted investigations have shown colocalization of DPR aggregates with specific proteins, suggesting mechanistic disruptions to related endogenous pathways may contribute to toxicity: GA has been reported to interact with Drosha, Unc119, HR23B (May et al., 2014; Porta et al., 2015; Zhang et al., 2016); GR has been reported to interact with eIF3B (also called eIF3q), STAU2, and multiple ribosomal proteins, including S6, S25, L19, L21, L36A (Hartmann et al., 2018; Y.-J. Zhang et al., 2018). Despite these findings and the observation that DPR aggregation predominantly occurs in neurons (versus glia), potential positive correlations between DPR expression and disease still need to be defined. Since the discovery of the repeat expansion in C9orf72-ALS/FTD, multiple studies have reported that the frequency of DPR aggregates does not correlate with degenerating tissue or clinical symptoms (i.e. age-of-onset, disease progression, disease severity) (Babić Leko et al., 2019; Vatsavayai et al., 2019). Only recently have two compelling studies described positive correlations between GR, but not the other DPRs, and diseased tissue (Saberi et al., 2018; Sakae et al., 2018). Overall, it is evident that additional, systematic investigations are needed, while consideration of multiple factors may help clarify results (i.e. disease stage, soluble versus insoluble DPR).

3. TRANSLATION OF G4C2ǁG2C4 REPEAT EXPANSIONS

As mentioned, G4C2ǁG2C4-repeat RNA can undergo a process termed repeat-associated non-AUG (RAN) translation to produce five dipeptides (DPR): GA, GR, GP, PA, PR (Fig. 1C). Specific dipeptides are particularly toxic in model systems, suggesting that a potential therapeutic approach could be to target translation of repeat-containing RNAto disrupt dipeptide expression. In fact, a number of small molecules have been proposed that interact with G-quadruplex and hairpin structures formed by G4C2-RNA (Simone et al., 2018; Su et al., 2014; Wang et al., 2019). Data ex vivo and in vivo show that these molecules can reduce RNA foci formation, dipeptide levels and G4C2-induced toxicity. Below we discuss current literature on G4C2ǁG2C4 RAN-translation, drawing parallels between multiple repeat-expansion associated diseases to propose a potential mechanism for RAN-translation.

3.1. Canonical versus non-canonical translation

Canonical translation involves multiple stages: initiation, elongation, and termination (Browning and Bailey-Serres, 2015; Marygold et al., 2017; Shatsky et al., 2018; Sonenberg and Hinnebusch, 2009). Of these, initiation is highly regulated and requires a large number of translation factors, termed eukaryotic initiation factors (eIFs). Translation initiation involves the formation of two main complexes: a ternary complex and a preinitiation complex (PIC). eIF5-mediates ternary complex formation between the eIF2 complex (subunits: eIF2α, eIF2β, eIF2γ) and initiator methionine-transfer ribonucleic acid (Met-tRNA,). This complex then forms the PIC with the 40S ribosome and eIFs eIF1, eIF1A, eIF5, eIF3 (a large, multi-subunit complex); a process mediated by multiple translation factors including eIF2A. For translation to initiate, another complex, the eIF4F complex (subunits: eIF4E, eIF4G, eIF4A), recognizes the 5′ m7G cap on a template mRNA. Specifically, eIF4E recognizes the cap, recruits the scaffold protein eIF4G, which then recruits eIF4A, an RNA helicase. The helicase activity of eIF4A unwinds secondary structures formed by the mRNA, an activity that is significantly stimulated by one of two RNA-binding proteins: eIF4B or eIF4H. The exposed mRNA then interacts with the PIC and the 48S scanning complex forms. Scanning of the mRNA continues 5′ to 3′ until a start codon is identified. This triggers the 48S scanning complex to release many of the eIFs and bind the 60S ribosome, forming the elongating 80S ribosome (subunits: 40S and 60S ribosomes; subunits are composed of multiple ribosomal proteins (Browning and Bailey-Serres, 2015)). The transition into elongation is further stimulated by eIF5B and, potentially, eIF5. During elongation, a relatively small number of eukaryotic elongation factors (eEFs) associate with the 80S ribosome to aid in productive translation.

Interestingly, non-canonical forms of translation occur under multiple normal and disease-associated contexts, of which internal ribosome entry-site (IRES) translation is well studied (Godet et al., 2019; Leppek et al., 2018; Shatsky et al., 2018; Terenin et al., 2017). The pathway underlying IRES-translation varies dramatically between situations. In many cases, IRES-translation is cap-independent and circumvents canonical translation initiation steps. A common theme is that translation initiation requires a minimal PIC complex, including only a small number of specific translation factors and the 40S ribosome. Further, secondary structure formation within the 5′ untranslated-region (UTR) of RNA templates plays an important role in the recruitment of translation initiation machinery.

Like IRES-translation, disease-associated RAN-translation also seems to depend on secondary structures and/or unique features within the 5′ UTR. The initial paper describing RAN-translation looked at peptide formation from expanded CAGǁCTG-repeats associated with spinocerebellar ataxia type 8 (SCA8) and myotonic dystrophy type 1 (DM1) (Zu et al., 2011). Zu and colleagues found that peptides were formed from repeat RNAs in the absence of a canonical AUG codon in a manner that was repeat-length dependent, with increasing numbers of repeats causing higher levels of peptide expression. Interestingly, translation required the formation of a hairpin structure – in contrast to (CAG)100+ repeats, (CAA)100+ repeats did not form hairpins nor undergo translation. Other studies on CGG-repeat expansions associated with fragile X-associated tremor ataxia syndrome (FXTAS) utilizing Drosophila and tissue-culture models showed that RAN-translation in this context initiates upstream of the repeat in a 5′ UTR region containing a non-canonical CUG start codon (Kearse et al., 2016; Todd et al., 2013).

3.2. Properties of G4C2-RNA that may influence RAN-translation

While mechanisms underlying G4C2-associated RAN-translation are relatively undefined, recent studies have begun to uncover critical variables. Drawing parallels between CGG- and G4C2-associated RAN-translation, Todd and colleagues used a novel ex vivo reporter system to show that G4C2-RAN translation requires the cap-recognizing factor eIF4E, and, subsequently, eIF4A (Green et al., 2017). The dependence of G4C2-RAN translation on eIF4E and eIF4A was validated by another research group using an independent ex vivo model (Tabet et al., 2018). Moreover, Tabet and colleagues showed that eIF4G, the scaffold protein between eIF4E and eIF4A, was required. To date, multiple studies have demonstrated that G4C2-RAN translation is promoted by the presence of a near-cognate CUG start codon within the GA-reading frame (Green et al., 2017; Sonobe et al., 2018; Tabet et al., 2018). This CUG is found in the G4C2-RNA transcript, upstream of the G4C2-repeat within the intronic RNA (sequence derived from intron 1 of C9orf72 and found upstream of G4C2-repeats in patients). Frame-shifting subsequent to translation initiation at this CUG is predicted to lead to the production of the multiple dipeptides from the G4C2-RNA (Tabet et al., 2018).

In addition to studies showing the dependence of G4C2-RAN translation on cap-recognizing eIF4F complex components – eIF4E, eIF4G, and eIF4A – translation may also be promoted by stress responses that inhibit cap-dependent translation (Cheng et al., 2018; Green et al., 2017; Tabet et al., 2018; Westergard et al., 2019). During neuronal stress, the integrated stress response (ISR) is triggered, resulting in eIF2α phosphorylation and activation of pathways hypothesized to protect the cell during conflict, such as stress granule formation, which sequesters cap-dependent translation machinery (Moon et al., 2018). Under stress, cap-independent translation can persist, allowing for the expression of proteins that help protect the cell (such as heat-shock proteins) (Godet et al., 2019; Shatsky et al., 2018). Interestingly, multiple studies have shown that triggering the ISR can stimulate dipeptide production from expanded G4C2-RNA (Cheng et al., 2018; Green et al., 2017; Sonobe et al., 2018; Westergard et al., 2019). Further, translation of G4C2-RNA can occur independent of a 5′ cap (Cheng et al., 2018). Moreover, a feed-forward loop may occur with G4C2-expression triggering the ISR, potentially the result of GR dipeptide associated mechanisms (Hartmann et al., 2018; Tao et al., 2015; Y.-J. Zhang et al., 2018).

Overall, a considerable variable when discussing G4C2-RAN translation is that the G4C2-RNA may exist in multiple forms in patients (Fig. 1B): a properly spliced intron, aborted transcripts, or a retained intron. Each of these forms of RNA may undergo RAN-translation by different mechanisms. Speculatively, one pathway may require the 5′ m7G cap and is predicted to impact G4C2-RNA still retained within the C9orf72-transcript. Another pathway may initiate in a cap-independent manner, predicted to impact G4C2-RNA that is within a properly spliced intron or aborted C9orf72-transcript. Pertaining to the intron retention model, one study suggested that if the G4C2-containing intron were retained in C9orf72-transcripts, then RAN-translation may be significantly downregulated or inhibited by upstream sequences found within exon 1a of the C9orf72 gene (Tabet et al., 2018). Another study utilized exon 1a-containing constructs to study RAN-translation where this process was not inhibited (Westergard et al., 2019); however, the rate of translation could be impacted under this scenario. Further, RAN translation can persist in the presence of a properly spliced intron containing the G4C2-repeat expansion (Cheng et al., 2018; Tran et al., 2015). When the G4C2-RNA existed in this form, its translation was promoted by the ISR (Cheng et al., 2018).

While conflicting data may be technical and not biological (different G4C2-models differ in construct design, cell type used for study, and the expression level of the constructs), these studies have offered initial mechanistic insights into G4C2-RAN translation. Current data suggest that G4C2-RAN translation may involve multiple pathways and may vary between cell types. Further investigations in cells and in animal models will help to define if/how progressive stress impacts RAN-translation, while shedding light on relevant C9+ disease mechanisms.

3.3. Potential G4C2-RAN translation factors and mechanisms

While continued investigations into mechanisms underlying G4C2ǁG2C4-RAN translation are underway, a short-list of translation factors has been proposed that may mediate this process (Figure 3). As noted, multiple studies have implicated the eIF4F complex as an important player. Depletion or inhibition of the subunits of eIF4F–eIF4E, eIF4G, eIF4A–causes reduced GA, GP, and GR production from G4C2-transcripts in ex vivo models. In addition, eIF2α has been proposed by multiple groups to promote the ISR and increase GA, GP, and GR production, although the pathway underlying this effect needs elucidation (Cheng et al., 2018; Green et al., 2017; Sonobe et al., 2018). eIF2A may also mediate dipeptide production from G4C2-RNA transcripts, as its downregulation in cells and chick embryos reduced GA-dipeptide levels (Sonobe et al., 2018). In addition to studies on G4C2ǁG2C4-RAN translation, a study focused on CAGǁCTG-disease identified eIF3F, a component of the eIF3 complex, for a role in RAN translation from CAG-repeats and potentially G4C2-repeats (Ayhan et al., 2018). Last, a component of the 40S ribosomal subunit, RpS25, has recently been implicated in RAN-translation from both G4C2ǁG2C4- and CAG-repeat containing RNAs (Yamada et al., 2019).

Figure 3: A model for G4C2 RAN-translation of GR-dipeptides noting factors shown to play a role in studies in vitro or in vivo.

Figure 3:

Open in a new tab

Comparisons between canonical translation and RAN-translation based on current literature and known functions of translation factors. Note that mechanisms underlying RAN-translation are still relatively unknown. Unless otherwise shown, RAN-translation factors have been assayed in cell culture models (ex vitro).A. In normal translation and potentially in RAN-translation, ternary complex formation requires eIF5-mediated exchange of GDP to GTP on eIF2 complex (includes eIFs 2α, 2β, 2γ). eIF2α is highly regulated during stress and is reported to mediate G4C2 and CGG translation, impacting multiple reading frames (Cheng et al., 2018; Green et al., 2017). eIF2ϐ and eIF5 were identified as potential modifiers in Drosophila, in a study focused on the GR-reading frame of G4C2-repeats (Goodman et al., 2019). B. In normal translation, the formation of the 43S pre-initiation complex (PIC) involves the joining of a number of factors, including the Ternary complex (formed in A) and eIFs 1, 1A, 3, and 5. Recruitment of the Ternary complex to the 40S ribosome is mediated by eIF2A or the eIF2 complex (not shown). eIF2A loss was shown to reduce GA-production from G4C2-RNA in culture and in chick embryos (Sonobe et al. 2018). The eIF3 complex is also important for PIC formation and is composed of multiple subunits, including eIF3F which has been defined as a RAN-translation factor in CAG and, potentially, G4C2 models (Ayhan et al., 2018). C. A minimal PIC complex may mediate RAN-translation, like in IRES translation, based on current studies. D. In canonical translation, eIF4E recognizes the 5-prime m7G cap on mRNAs; eIF4E has been described as a RAN-translation factor, impacting translation from both G4C2- and CGG-repeats (Goodman et al., 2019; Green et al., 2017; Kearse et al., 2016; Tabet et al., 2018) . In canonical translation, eIF4A is recruited by eIF4E to mRNA transcripts (via the scaffold protein eIF4G); both eIF4G and eIF4A have been described as RAN-translation factors (Green et al., 2017; Kearse et al., 2016; Tabet et al., 2018). eIF4A, a known helicase, may unwind the RNA, an activity that is significantly promoted by eIF4B or eIF4H. In support of their involvement in RAN-translation, loss of either eIF4B and eIF4H impacts GR-production from G4C2-repeats in Drosophila (Goodman et al., 2019). E. A scanning complex could then potentially form on the unwound RNA. In canonical translation, the 48S scanning complex moves down a transcript until identifying an AUG start codon. A CUG codon in the intronic sequence upstream of G4C2 repeat, termed leader sequence (LDS), may function as a start codon in the GA-reading frame (Green et al., 2017; Tabet et al., 2018). Frame-shifting could allow for translation of the GR and GP from this initiation site, although additional investigation on this and for other possible mechanisms is needed. F. A candidate RAN translation factor for G4C2-repeats also includes eIF5B (Goodman et al., 2019), which mediates ribosome scanning, start codon recognition, and translation activation in canonical translation. Thus, this factor may play a role in translation initiation during RAN translation. (Figure modified from Goodman et al., 2019.)

In order to shed light on translation factors that may be involved in the production of toxic-GR dipeptide in C9+ ALS/FTD, Goodman and colleagues took an unbiased, in vivo approach (Goodman et al., 2019). A fly model was developed that expressed an RNA with a toxic (G4C2)44 repeat, but retained 114 bp of the intronic RNA sequence found immediately upstream of the repeat in patients (Fig. 2A); a similar upstream region has been associated with RAN-translation of the repeat in cells and in viral mouse models (Chew et al., 2019, 2015; Mori et al., 2013b). A GFP tag lacking an AUG start codon was inserted immediately 3′ of the G4C2-repeats in the GR-reading frame, effectively tagging GR-dipeptides produced from the repeats with this fluorescent marker. The focus was on GR as its expression, independent of a G4C2-repeat RNA, is particularly toxic in model systems, including Drosophila (Freibaum et al., 2015; Mizielinska et al., 2014). No canonical start codons are within the construct, while the near-cognate CUG start codon present in the GA-reading frame was retained, thus mimicking C9+ ALS/FTD. By expressing this transgene within the fly eye, a rapid screen for genes that impacted GR-dipeptide levels produced from the (G4C2)44 by screening for both toxicity and expression of a GR-GFP protein was performed (Fig. 2B). Comparisons could then be made between GR-GFP levels and toxicity.

Figure 2: An unbiased screen in Drosophila revealed potential RAN-translation factors.

Figure 2:

Open in a new tab

A. Utilizing the GAL4/UAS expression system, a fly model was developed that expressed 114bp of intron 1 from human C9orf72 followed by an expanded (>30) G4C2-hexanucleotide repeat. A 3′ GFP tag was inserted within the GR-reading frame, effectively tagging this toxic dipeptide with a fluorescent marker. B. Using external eye imaging, 48 of 56 canonical translation factors were tested in the fly eye for those that impacted G4C2-toxicity and GR-GFP levels. 28 translation factors were further tested for effects in a fly model that expressed the toxic GR dipeptide from a non-G4C2 containing RNA to define factors acting on the peptide downstream of RAN-translation. C. eIF4H is downregulated in tissue derived from C9orf72 ALS/FTD patients. Shown is RNA data utilizing post-mortem cerebellar tissue from healthy individuals, ALS/FTD patients lacking the G4C2-expansion within C9orf72 (C9−) and ALS/FTD patients harboring the G4C2-expansion (C9+). (Modified from Goodman et al., 2019).

Using established loss-of-function mutant or RNAi transgenic fly lines and this more patient-relevant (G4C2)44 fly model, 48 of 56 (86%) known translation factors were screened for their ability to alter GR-GFP production and G4C2-induced toxicity (Goodman et al., 2019). The screen included factors involved in multiple stages of translation: initiation, elongation, and termination (Marygold et al., 2017). After control experiments to rule out factors conferring nonspecific effects and/or acting downstream of toxic GR-peptide, 11 candidate RAN-translation factors were identified: eIF4B, eIF4H, eIF5B, eIF5, eIF2ϐ, eIF3D1, eIF3I, and multiple orthologuesto eIF4E (E3, E4, E5, E7). Intrigu ingly, most of the factors identified act with, or are orthologuesto, previously proposed RAN-translation factors: eIF4F components and eIF2α (Fig. 3). eIF4B and eIF4H were the focus of further investigations as these two proteins have non-redundant roles in stimulating eIF4A-helicase activity (García-García et al., 2015; Harms et al., 2014; Nielsen et al., 2011; Rogers et al., 2001; Rozovsky et al., 2008; Sen et al., 2016; Sun et al., 2012; Vaysse et al., 2015). These two factors behaved in a manner consistent with a function in G4C2-RAN translation: their depletion reduced G4C2-toxicity, reduced GR-levels produced from G4C2-RNA, did not alter G4C2-RNA levels, did not reduce toxicity caused by GR-dipeptides. Pertinent to disease, eIF4B and eIF4H contain an RNA recognition motif and were previously shown to interact with G4C2-containing RNA (Cooper-Knock et al., 2014; Haeusler et al., 2014; Satoh et al., 2014). Further, eIF4H, but not eIF4B, was downregulated in C9+ derived cells and in post-mortem C9+ ALS/FTD tissue, compared to C9- ALS/FTD and healthy tissue, arguing that eIF4H downregulation was a response to expression of the G4C2 expansion within C9orf72 (Fig. 2C).

The importance of eIF4B/H-mediated activation of eIF4A in G4C2-RAN translation is supported by the observation that G4C2-RNA can form unique secondary structures (Brázda et al., 2014; Nishida et al., 2017; Simone et al., 2015). G-quadruplexes and hairpins formed by GC-rich RNA can inhibit translation and thus require resolution (Fay et al., 2017b; Maizels, 2015; Wang et al., 2018). Notably, eIF4A was previously shown to promote translation from RNA transcripts predicted to form G-quadruplexes, presumably by resolving these secondary structures (Wolfe et al., 2014). Fittingly, stabilizing G4C2-RNA quadruplexes/hairpins with small molecules can inhibit dipeptide production and downstream toxic effects (Simone et al., 2018; Su et al., 2014; Wang et al., 2019); this indicates that resolving these structures would be needed to allow translation to occur. Interestingly, the ability of eIF4A to unwind longer, more structured 5′ UTRs on transcripts is significantly strengthened by eIF4B or eIF4H (Rozovsky et al., 2008; Sen et al., 2016; Sun et al., 2012; Vaysse et al., 2015). Unwound RNA can then interact with ribosomes and the 43S scanning complex (Sharma et al., 2015; Spirin, 2009; Walker et al., 2013). Overall, these data support a model whereby eIF4A is recruited to G4C2-RNA, potentially by eIF4E/G (Fig. 3D). Then, with the help of eIF4B/H, eIF4A is able to unwind the secondary structures formed by G4C2-RNA, thus allowing the PIC to interact with the RNA template and promoting scanning by the 48S scanning complex until reaching a translation start site, potentially the near-cognate CUG in the GA reading frame (Green et al., 2017; Tabet et al., 2018). Speculatively, frameshifting could lead to production of the GR-dipeptide under this model. Alternatively, dipeptides could be generated by cap-independent translation still requiring eIF4A activity to unwind the RNA, as in IRES translation (Khan and Goss, 2012; Komar and Flatzoglou, 2011; Sharma et al., 2015; Vaysse et al., 2015).

This unbiased approach in the fly highlighted additional factors that may be important for G4C2-associated RAN-translation. Notably, of the 48 translation factors screened, only downregulation of a subset impacted GR-production from G4C2-transcripts. This argues that, like with IRES translation, RAN translation can circumvent canonical translation steps and may utilize only a small number of translation factors.

4. IMPLICATIONS FOR OTHER REPEAT-EXPANSION DISEASES

In addition to G4C2-repeats, RNA-transcripts produced in other repeat-expansion diseases can also undergo RAN-translation. As noted, CAG repeats can produce three peptides, depending on the reading frame (Zu et al., 2011). Interestingly, peptide production was dependent on repeat-length and the ability of the RNA to form hairpin structures, like those potentially formed by G4C2 RNA. Moreover, CGG-repeats can produce peptides through mechanisms independent of an AUG-start codon (Kearse et al., 2016; Todd et al., 2013). These repeats can also form stable hairpins which may mediate RAN-translation to produce peptides (Sobczak et al., 2010; Zu et al., 2011). Recently, Todd and colleagues drew parallels between CGG- and G4C2-RAN translation mechanisms, highlighting that both require eIF4E and eIF4A (Green et al., 2017; Kearse et al., 2016). Intriguingly, the fly studies in vivo highlight a role for eIF4B and eIF4H in G4C2-RAN translation (Goodman et al., 2019), while these two factors act on eIF4A to promote unwinding of secondary structures formed by RNA (García-García et al., 2015; Harms et al., 2014; Nielsen et al., 2011; Rogers et al., 2001; Rozovsky et al., 2008; Sen et al., 2016; Sun et al., 2012; Vaysse et al., 2015). This activity of eIF4B and eIF4H is particularly important at highly structured, repetitive RNA sequences. Thus, it is reasonable to hypothesize that these two factors may also play a role in CGG- and/or CAG-RAN translation. The connection between G4C2-, CGG-, and CAG-RAN translation may be their ability to form unique hairpin structures.

In total, data support that the translation factors identified thus far as potential G4C2 RAN-translation factors may also be important in other repeat-associated diseases. Overall, defining common mechanisms underlying RAN-translation could highlight potential therapeutic targets universal to multiple, related diseases while increasing understandings of this unique process. Taking lessons from chemotherapies in cancer, one would need to carefully titer any inhibition of canonical translation machinery so that there are beneficial effects in disease while not significantly impairing normal/healthy cells.

5. IMPLICATIONS IN MULTIPLE ASPECTS OF C9-ALS/FTD

Thus far, we have focused on the role of translation factors in disease as potential regulators of RAN-translation. Here we will briefly discuss other potential pathways of translation that may impact in disease, focusing on ALS/FTD.

In ALS/FTD, prolonged stress granule formation has been a focus as a contributing disease mechanism (Fernandes et al., 2018; Guzikowski et al., 2019). Stress granules are cytoplasmic messenger ribonucleoprotein (mRNP) assemblies that form under stress and are predicted to be neuroprotective. During stress situations, specific canonical translation machinery, proteins (e.g. RNA-binding proteins) and mRNAs collect into these dynamic foci, effectively stalling cap-dependent AUG-driven translation and saving energy and resources until the stress is relieved. Interestingly, not all eIFs are integrated into stress granules, potentially leaving them available to mediate cap-independent translation of protective proteins like chaperones (Advani and Ivanov, 2019; Godet et al., 2019; Guzikowski et al., 2019). Notably, eIF2α is excluded and is a regulator of stress granule formation – its phosphorylation/inhibition can stimulate stress granule assembly and its dephosphorylation/activation is associated with stress granule disassembly (Advani and Ivanov, 2019; Moon et al., 2018). As noted, eIF2α may be a player in RAN-translation (Cheng et al., 2018; Green et al., 2017). Among other translation factors that may mediate RAN-translation, eIF2β and eIF5 may also be excluded from stress granules (Buchan and Parker, 2009; Kedersha et al., 2002). Others are found in stress granules, while eIF4H requires further investigation. An interesting, potential connection between stress granule formation in C9-ALS/FTD and the G4C2-expanded repeat is found with eIF4H downregulation in C9+ derived patient cells and tissue (Goodman et al., 2019). eIF4B/H depletion induces stress granule assembly (Ayuso et al., 2016; Mokas et al., 2009). Further, expression of G4C2-RNA can induce stress granules in model systems (Chew et al., 2019; Fay et al., 2017a; Green et al., 2017; Rossi et al., 2015). Overall, data suggest that eIF4H downregulation in G4C2-expressing tissue may be connected to stress granule formation, effectively the inhibition of general translation, and potentially the accumulation of TDP-43 aggregates in C9+ disease which may be promoted by stress granules (Chew et al., 2019, 2015; Solomon et al., 2018). Whether this effect is dependent on the presence of the G4C2-RNA versus its dipeptide products is currently unclear, as dipeptide expression can induce stress granules and inhibit AUG-driven translation (Boeynaems et al., 2017; Chew et al., 2019; Kanekura et al., 2016; Lee et al., 2016; Treeck et al., 2018; Yamakawa et al., 2015; Y.-J. Zhang et al., 2018).

An interesting finding of the unbiased screen in the fly eye is that loss of specific translation factors increased GR-induced toxicity (Goodman et al., 2019). Dipeptide-mediated inhibition of general translation could be a complex, multi-step process that may not be dependent on stress-granule assembly. Studies have argued that the dipeptides can directly interact with nucleolar proteins, ribosomes, and other translation machinery to inhibit translation (Hartmann et al., 2018; Kwon et al., 2014; Lee et al., 2016; Mizielinska et al., 2017; O’Rourke et al., 2015; Tao et al., 2015; Wen et al., 2014; Y.-J. Zhang et al., 2018). Further, mRNA trafficking may be impacted by expression of the G4C2-RNA in disease (Boeynaems et al., 2016; Freibaum et al., 2015; Jovičić et al., 2015; Rossi et al., 2015; K. Zhang et al., 2018; Zhang et al., 2015), potentially resulting in reduced mRNA availability for general translation within the cytoplasm. Thus, it is possible that the translation factors whose depletion increased GR-toxicity may play important roles in dipeptide-mediated inhibition of general translation. Fittingly, eIF3B (also known as eIF3η) was shown to interact with GR-dipeptides in mice (K. Zhang et al., 2018), while the fly screen revealed that loss of this factor could enhance GR-toxicity (Goodman et al., 2019).

Overall, further studies into mechanisms underlying RAN-translation are essential for increasing our understanding of the G4C2-mutation in disease. However, multiple aspects of translation factor mis-regulation need to be considered, such as induction of stress-pathways and impact on general translation, before pursuing translational machinery as a potential therapeutic target.

6. CONCLUDING REMARKS

Elucidation of mechanisms underlying RAN-translation will provide essential understanding of this unique biological process in normal biology and in disease. While current studies are focused on the G4C2-repeat associated with ALS/FTD, it is likely that commonalities exist between the various diseases that include translation of repeat-containing RNA to produce unique peptide products. As described, initial work is utilizing information derived from canonical and non-canonical (e.g. IRES) translation to uncover unique features of the repeat-containing RNA and translation factors that may be involved. Further investigations will need to delve deeper into the process to determine whether additional translation factors and proteins, such as specific RNA-binding proteins, or if RNA modification(s), such as m6A methylation, are also integral contributors to RAN-translation mechanism(s). An understanding of how RAN-translation is related to cap-independent translation may also shed light on normal cellular processes, such as the expression of protective proteins during stress situations.

Supplementary Material

1

OUTLINE.

  1. C9orf72-mutation in ALS/FTD disease: a hexanucleotide-repeat expansion
    1. What is ALS/FTD
    2. What is this mutation
    3. An overview of current disease mechanisms, focusing on whether dipeptides contribute to toxicity and conflicting pathology data in patients and data from model systems
  2. An introduction to Repeat Associated non-AUG translation.
    1. Repeat expansion diseases
    2. Discovery of RAN.
  3. Translation of G4C2 repeat expansions
    1. evidence for translation
    2. variables that impact RAN translation.
      1. impact of stress
      2. existence of multiple RNA transcripts containing the G4C2 repeats in disease (intron retained within mRNA; spliced intron; aborted transcripts)
      3. 5′ region upstream of the repeat
      4. Formation of secondary structures (hairpins)
    3. canonical translation factors reported to mediate G4C2 RAN-translation/implications for mechanism.
    4. A potential model for G4C2 repeat translation, contrasting with canonical translation
  4. Implications in ALS/FTD disease
    1. potential functions of factors in disease beyond RAN-translation
    2. potential connections to stress granules and TDP-43 pathology

  5. Implications of these findings to other nucleotide-repeat expansion associated diseases

Acknowledgments

This work was funded by the Systems and Integrative Biology NIH/NIGMS training grant T32-GM07517 (to L.D.G.), NIH/NINDS R01-NS078283 (to N.M.B.), and NIH/NINDS R35-NS09727 (to N.M.B.).

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Competing interests

The authors declare that they have no conflicts of interest with the contents of this article.

REFERENCES

  1. Advani VM, Ivanov P, 2019. Translational Control under Stress: Reshaping the Translatome. BioEssays 41, 1900009 10.1002/bies.201900009 [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Al-Chalabi A, Hardiman O, 2013. The epidemiology of ALS: a conspiracy of genes, environment and time. Nature Reviews Neurology 9, 617 10.1038/nrneurol.2013.203 [DOI] [PubMed] [Google Scholar]
  3. Ash PEA, Bieniek KF, Gendron TF, Caulfield T, Lin W-L, DeJesus-Hernandez M, van Blitterswijk MM, Jansen-West K, Paul JW, Rademakers R, Boylan KB, Dickson DW, Petrucelli L, 2013. Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron 77, 639–646. 10.1016/j.neuron.2013.02.004 [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Atanasio A, Decman V, White D, Ramos M, Ikiz B, Lee H-C, Siao C-J, Brydges S, LaRosa E, Bai Y, Fury W, Burfeind P, Zamfirova R, Warshaw G, Orengo J, Oyejide A, Fralish M, Auerbach W, Poueymirou W, Freudenberg J, Gong G, Zambrowicz B, Valenzuela D, Yancopoulos G, Murphy A, Thurston G, Lai K-MV, 2016. C9orf72 ablation causes immune dysregulation characterized by leukocyte expansion, autoantibody production, and glomerulonephropathy in mice. Sci Rep 6 10.1038/srep23204 [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Ayhan F, Perez BA, Shorrock HK, Zu T, Banez-Coronel M, Reid T, Furuya H, Clark HB, Troncoso JC, Ross CA, Subramony S, Ashizawa T, Wang ET, Yachnis AT, Ranum LP, 2018. SCA8 RAN polySer protein preferentially accumulates in white matter regions and is regulated by eIF3F. The EMBO Journal 37, e99023 10.15252/embj.201899023 [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Ayuso MI, Martínez-Alonso E, Regidor I, Alcázar A, 2016. Stress Granule Induction after Brain Ischemia Is Independent of Eukaryotic Translation Initiation Factor (eIF) 2α Phosphorylation and Is Correlated with a Decrease in eIF4B and eIF4E Proteins. J. Biol. Chem 291, 27252–27264. 10.1074/jbc.M116.738989 [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Babić Leko M, Župunski V, Kirincich J, Smilović D, Hortobágyi T, Hof PR, Šimić G, 2019. Molecular Mechanisms of Neurodegeneration Related to C9orf72 Hexanucleotide Repeat Expansion [WWW Document], Behavioural Neurology, 10.1155/2019/2909168 [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Balendra R, Isaacs AM, 2018. C9orf72 -mediated ALS and FTD: multiple pathways to disease. Nature Reviews Neurology 14, 544 10.1038/s41582-018-0047-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Belzil VV, Bauer PO, Gendron TF, Murray ME, Dickson D, Petrucelli L, 2014. Characterization of DNA hypermethylation in the cerebellum of c9FTD/ALS patients. Brain Res. 1584, 15–21. 10.1016/j.brainres.2014.02.015 [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Boeynaems S, Bogaert E, Kovacs D, Konijnenberg A, Timmerman E, Volkov A, Guharoy M, De Decker M, Jaspers T, Ryan VH, Janke AM, Baatsen P, Vercruysse T, Kolaitis R-M, Daelemans D, Taylor JP, Kedersha N, Anderson P, Impens F, Sobott F, Schymkowitz J, Rousseau F, Fawzi NL, Robberecht W, Van Damme P, Tompa P, Van Den Bosch L, 2017. Phase Separation of C9orf72 Dipeptide Repeats Perturbs Stress Granule Dynamics. Molecular Cell 65, 1044–1055.e5. 10.1016/j.molcel.2017.02.013 [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Boeynaems S, Bogaert E, Michiels E, Gijselinck I, Sieben A, Jovičić A, De Baets G, Scheveneels W, Steyaert J, Cuijt I, Verstrepen KJ, Callaerts P, Rousseau F, Schymkowitz J, Cruts M, Van Broeckhoven C, Van Damme P, Gitler AD, Robberecht W, Van Den Bosch L, 2016. Drosophila screen connects nuclear transport genes to DPR pathology in c9ALS/FTD. Scientific Reports 6, 20877 10.1038/srep20877 [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Brázda V, Hároníková L, Liao JCC, Fojta M, 2014. DNA and RNA Quadruplex-Binding Proteins. International Journal of Molecular Sciences 15, 17493 10.3390/ijms151017493 [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Browning KS, Bailey-Serres J, 2015. Mechanism of Cytoplasmic mRNA Translation. Arabidopsis Book 13 10.1199/tab.0176 [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Buchan JR, Parker R, 2009. Eukaryotic Stress Granules: The Ins and Out of Translation. Mol Cell 36, 932 10.1016/j.molcel.2009.11.020 [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Buchman VL, Cooper-Knock J, Connor-Robson N, Higginbottom A, Kirby J, Razinskaya OD, Ninkina N, Shaw PJ, 2013. Simultaneous and independent detection of C9ORF72 alleles with low and high number of GGGGCC repeats using an optimised protocol of Southern blot hybridisation. Molecular Neurodegeneration 8, 12 10.1186/1750-1326-8-12 [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Česnik AB, Darovic S, Mihevc SP, Štalekar M, Malnar M, Motaln H, Lee Y-B, Mazej J, Pohleven J, Grosch M, Modic M, Fonovič M, Turk B, Drukker M, Shaw CE, Rogelj B, 2019. Nuclear RNA foci from C9ORF72 expansion mutation form paraspeckle-like bodies. J Cell Sci jcs.224303. 10.1242/jcs.224303 [DOI] [PubMed] [Google Scholar]
  17. Cheng W, Wang S, Mestre AA, Fu C, Makarem A, Xian F, Hayes LR, Lopez-Gonzalez R, Drenner K, Jiang J, Cleveland DW, Sun S, 2018. C9ORF72 GGGGCC repeat-associated non-AUG translation is upregulated by stress through eIF2α phosphorylation. Nature Communications 9, 51 10.1038/s41467-017-02495-z [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Chew J, Cook C, Gendron TF, Jansen-West K, del Rosso G, Daughrity LM, Castanedes-Casey M, Kurti A, Stankowski JN, Disney MD, Rothstein JD, Dickson DW, Fryer JD, Zhang Y-J, Petrucelli L, 2019. Aberrant deposition of stress granule-resident proteins linked to C9orf72-associated TDP-43 proteinopathy. Molecular Neurodegeneration 14, 9 10.1186/sl3024-019-0310-z [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Chew J, Gendron TF, Prudencio M, Sasaguri H, Zhang Y-J, Castanedes-Casey M, Lee CW, Jansen-West K, Kurti A, Murray ME, Bieniek KF, Bauer PO, Whitelaw EC, Rousseau L, Stankowski JN, Stetler C, Daughrity LM, Perkerson EA, Desaro P, Johnston A, Overstreet K, Edbauer D, Rademakers R, Boylan KB, Dickson DW, Fryer JD, Petrucelli L, 2015. C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits. Science 348, 1151–1154. 10.1126/science.aaa9344 [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Chitiprolu M, Jagow C, Tremblay V, Bondy-Chorney E, Paris G, Savard A, Palidwor G, Barry FA, Zinman L, Keith J, Rogaeva E, Robertson J, Lavallée-Adam M, Woulfe J, Couture J-F, Côté J, Gibbings D, 2018. A complex of C9ORF72 and p62 uses arginine methylation to eliminate stress granules by autophagy. Nature Communications 9, 2794 10.1038/s41467-018-05273-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Ciura S, Lattante S, Le Ber I, Latouche M, Tostivint H, Brice A, Kabashi E, 2013. Loss of function of C9orf72 causes motor deficits in a zebrafish model of amyotrophic lateral sclerosis. Annals of Neurology 74, 180–187. 10.1002/ana.23946 [DOI] [PubMed] [Google Scholar]
  22. Cook C, Petrucelli L, 2019. Genetic Convergence Brings Clarity to the Enigmatic Red Line in ALS. Neuron 101, 1057–1069. 10.1016/j.neuron.2019.02.032 [DOI] [PubMed] [Google Scholar]
  23. Cooper-Knock J, Bury JJ, Heath PR, Wyles M, Higginbottom A, Gelsthorpe C, Highley JR, Hautbergue G, Rattray M, Kirby J, Shaw PJ, 2015a. C9ORF72 GGGGCC Expanded Repeats Produce Splicing Dysregulation which Correlates with Disease Severity in Amyotrophic Lateral Sclerosis. PLoSOne 10 10.1371/journal.pone.0127376 [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Cooper-Knock J, Higginbottom A, Stopford MJ, Highley JR, Ince PG, Wharton SB, Pickering-Brown S, Kirby J, Hautbergue GM, Shaw PJ, 2015b. Antisense RNA foci in the motor neurons of C9ORF72-ALS patients are associated with TDP-43 proteinopathy. Acta Neuropathol 130, 63–75. 10.1007/s00401-015-1429-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Cooper-Knock J, Walsh MJ, Higginbottom A, Robin Highley J, Dickman MJ, Edbauer D, Ince PG, Wharton SB, Wilson SA, Kirby J, Hautbergue GM, Shaw PJ, 2014. Sequestration of multiple RNA recognition motif-containing proteins by C9orf72 repeat expansions. Brain 137, 2040–2051. 10.1093/brain/awul20 [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Davidson YS, Barker H, Robinson AC, Thompson JC, Harris J, Troakes C, Smith B, Al-Saraj S, Shaw C, Rollinson S, Masuda-Suzukake M, Hasegawa M, Pickering-Brown S, Snowden JS, Mann DM, 2014. Brain distribution of dipeptide repeat proteins in frontotemporal lobar degeneration and motor neurone disease associated with expansions in C9ORF72. Acta Neuropathol Commun 2 10.1186/2051-5960-2-70 [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, Nicholson AM, Finch NA, Gilmer HF, Adamson J, Kouri N, Wojtas A, Sengdy P, Hsiung G-YR, Karydas A, Seeley WW, Josephs KA, Coppola G, Geschwind DH, Wszolek ZK, Feldman H, Knopman D, Petersen R, Miller BL, Dickson D, Boylan K, Graff-Radford N, Rademakers R, 2011. Expanded GGGGCC hexanucleotide repeat in non-coding region of C9ORF72 causes chromosome 9p-linked frontotemporal dementia and amyotrophic lateral sclerosis. Neuron 72, 245–256. 10.1016/j.neuron.2011.09.011 [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Dobson-Stone C, Hallupp M, Loy CT, Thompson EM, Haan E, Sue CM, Panegyres PK, Razquin C, Seijo-Martinez M, Rene R, Gascon J, Campdelacreu J, Schmoll B, Volk AE, Brooks WS, Schofield PR, Pastor P, Kwok JBJ, 2013. C9ORF72 Repeat Expansion in Australian and Spanish Frontotemporal Dementia Patients. PLOS ONE 8, e56899 10.1371/journal.pone.0056899 [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Edbauer D, Haass C, 2016. An amyloid-like cascade hypothesis for C9orf72 ALS/FTD. Current Opinion in Neurobiology, Neurobiology of disease 36, 99–106. 10.1016/j.conb.2015.10.009 [DOI] [PubMed] [Google Scholar]
  30. Farg MA, Sundaramoorthy V, Sultana JM, Yang S, Atkinson RAK, Levina V, Halloran MA, Gleeson PA, Blair IP, Soo KY, King AE, Atkin JD, 2014. C9ORF72, implicated in amytrophic lateral sclerosis and frontotemporal dementia, regulates endosomal trafficking. Hum Mol Genet 23, 3579–3595. 10.1093/hmg/ddu068 [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Fay MM, Anderson PJ, Ivanov P, 2017a. ALS/FTD-Associated C9ORF72 Repeat RNA Promotes Phase Transitions In Vitro and in Cells. Cell Reports 21, 3573–3584. 10.1016/j.celrep.2017.ll.093 [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Fay MM, Lyons SM, Ivanov P, 2017b. RNA G-quadruplexes in biology: principles and molecular mechanisms. J Mol Biol 429, 2127–2147. 10.1016/j.jmb.2017.05.017 [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Fernandes N, Eshleman N, Buchan JR, 2018. Stress Granules and ALS: A Case of Causation or Correlation?, in: Sattler R, Donnelly CJ (Eds.), RNA Metabolism in Neurodegenerative Diseases. Springer International Publishing, Cham, pp. 173–212. 10.1007/978-3-319-89689-2_7 [DOI] [PubMed] [Google Scholar]
  34. Freibaum BD, Lu Y, Lopez-Gonzalez R, Kim NC, Almeida S, Lee K-H, Badders N, Valentine M, Miller BL, Wong PC, Petrucelli L, Kim HJ, Gao F-B, Taylor JP, 2015. GGGGCC repeat expansion in C9ORF72 compromises nucleocytoplasmic transport. Nature 525, 129–133. 10.1038/nature14974 [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Freibaum BD, Taylor JP, 2017. The Role of Dipeptide Repeats in C9ORF72-Related ALS-FTD. Front Mol Neurosci 10 10.3389/fnmol.2017.00035 [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Frick P, Sellier C, Mackenzie IRA, Cheng C-Y, Tahraoui-Bories J, Martinat C, Pasterkamp RJ, Prudlo J, Edbauer D, Oulad-Abdelghani M, Feederle R, Charlet-Berguerand N, Neumann M, 2018. Novel antibodies reveal presynaptic localization of C9orf72 protein and reduced protein levels in C9orf72 mutation carriers. Acta Neuropathologica Communications 6, 72 10.1186/s40478-018-0579-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. García-García C, Frieda KL, Feoktistova K, Fraser CS, Block SM, 2015. Factor-dependent processivity in human eIF4A DEAD-box helicase. Science 348, 1486–1488. 10.1126/science.aaa5089 [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Gendron TF, Bieniek KF, Zhang Y-J, Jansen-West K, Ash PEA, Caulfield T, Daughrity L, Dunmore JH, Castanedes-Casey M, Chew J, Cosio DM, van Blitterswijk M, Lee WC, Rademakers R, Boylan KB, Dickson DW, Petrucelli L, 2013. Antisense transcripts of the expanded C9ORF72 hexanucleotide repeat form nuclear RNA foci and undergo repeat-associated non-ATG translation in c9FTD/ALS. Acta Neuropathol. 126, 829–844. 10.1007/s00401-013-1192-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Gendron TF, Chew J, Stankowski JN, Hayes LR, Zhang Y-J, Prudencio M, Carlomagno Y, Daughrity LM, Jansen-West K, Perkerson EA, O’Raw A, Cook C, Pregent L, Belzil V, Blitterswijk M van, Tabassian LJ, Lee CW, Yue M, Tong J, Song Y, Castanedes-Casey M, Rousseau L, Phillips V, Dickson DW, Rademakers R, Fryer JD, Rush BK, Pedraza O, Caputo AM, Desaro P, Palmucci C, Robertson A, Heckman MG, Diehl NN, Wiggs E, Tierney M, Braun L, Farren J, Lacomis D, Ladha S, Fournier CN, McCluskey LF, Elman LB, Toledo JB, McBride JD, Tiloca C, Morelli C, Poletti B, Solca F, Prelle A, Wuu J, Jockel-Balsarotti J, Rigo F, Ambrose C, Datta A, Yang W, Raitcheva D, Antognetti G, McCampbell A, Swieten JCV, Miller BL, Boxer AL, Brown RH, Bowser R, Miller TM, Trojanowski JQ, Grossman M, Berry JD, Hu WT, Ratti A, Traynor BJ, Disney MD, Benatar M, Silani V, Glass JD, Floeter MK, Rothstein JD, Boylan KB, Petrucelli L, 2017. Poly(GP) proteins are a useful pharmacodynamic marker for C9ORF72-associated amyotrophic lateral sclerosis. Science Translational Medicine 9, eaai7866 10.1126/scitranslmed.aai7866 [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Gijselinck I, Van Langenhove T, van der Zee J, Sleegers K, Philtjens S, Kleinberger G, Janssens J, Bettens K, Van Cauwenberghe C, Pereson S, Engelborghs S, Sieben A, De Jonghe P, Vandenberghe R, Santens P, De Bleecker J, Maes G, Bäumer V, Dillen L, Joris G, Cuijt I, Corsmit E, Elinck E, Van Dongen J, Vermeulen S, Van den Broeck M, Vaerenberg C, Mattheijssens M, Peeters K, Robberecht W, Cras P, Martin J-J, De Deyn PP, Cruts M, Van Broeckhoven C, 2012. A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study. The Lancet Neurology 11, 54–65. 10.1016/S1474-4422(11)70261-7 [DOI] [PubMed] [Google Scholar]
  41. Godet A-C, David F, Hantelys F, Tatin F, Lacazette E, Garmy-Susini B, Prats A-C, 2019. IRES Trans-Acting Factors, Key Actors of the Stress Response. International Journal of Molecular Sciences 20, 924 10.3390/ijms20040924 [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Goodman LD, Prudencio M, Srinivasan AR, Rifai OM, Lee VM-Y, Petrucelli L, Bonini NM, 2019. eIF4B and eIF4H mediate GR production from expanded G4C2 in a Drosophila model for C9orf72-associated ALS. Acta Neuropathologica Communications 7, 62 10.1186/s40478-019-0711-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Green KM, Glineburg MR, Kearse MG, Flores BN, Linsalata AE, Fedak SJ, Goldstrohm AC, Barmada SJ, Todd PK, 2017. RAN translation at C9orf72-associated repeat expansions is selectively enhanced by the integrated stress response. Nat Commun 8 10.1038/s41467-017-02200-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Guzikowski AR, Chen YS, Zid BM, 2019. Stress-induced mRNP granules: Form and function of processing bodies and stress granules. Wiley Interdisciplinary Reviews: RNA 10, e1524 10.1002/wrna.1524 [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Haeusler AR, Donnelly CJ, Periz G, Simko EAJ, Shaw PG, Kim M-S, Maragakis NJ, Troncoso JC, Pandey A, Sattler R, Rothstein JD, Wang J, 2014. C9orf72 Nucleotide Repeat Structures Initiate Molecular Cascades of Disease. Nature 507, 195–200. 10.1038/nature13124 [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Harms U, Andreou AZ, Gubaev A, Klostermeier D, 2014. eIF4B, eIF4G and RNA regulate eIF4A activity in translation initiation by modulating the eIF4A conformational cycle. Nucleic Acids Res 42, 7911–7922. 10.1093/nar/gku440 [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Hartmann H, Hornburg D, Czuppa M, Bader J, Michaelsen M, Farny D, Arzberger T, Mann M, Meissner F, Edbauer D, 2018. Proteomics and C9orf72 neuropathology identify ribosomes as poly-GR/PR interactors driving toxicity. Life Science Alliance 1, e201800070 10.26508/lsa.201800070 [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Ho WY, Tai YK, Chang J-C, Liang J, Tyan S-H, Chen S, Guan J-L, Zhou H, Shen H-M, Koo E, Ling S-C, 2019. The ALS-FTD-linked gene product, C9orf72, regulates neuronal morphogenesis via autophagy. Autophagy 0, 1–16. 10.1080/15548627.2019.1569441 [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Hübers A, Marroquin N, Schmoll B, Vielhaber S, Just M, Mayer B, Högel J, Dorst J, Mertens T, Just W, Aulitzky A, Wais V, Ludolph AC, Kubisch C, Weishaupt JH, Volk AE, 2014. Polymerase chain reaction and Southern blot-based analysis of the C9orf72 hexanucleotide repeat in different motor neuron diseases. Neurobiol. Aging 35, 1214.e1–6. 10.1016/j.neurobiolaging.2013.11.034 [DOI] [PubMed] [Google Scholar]
  50. Ito D, Hatano M, Suzuki N, 2017. RNA binding proteins and the pathological cascade in ALS/FTD neurodegeneration. Science Translational Medicine 9, eaah5436 10.1126/scitranslmed.aah5436 [DOI] [PubMed] [Google Scholar]
  51. Ji A-L, Zhang X, Chen W-W, Huang W-J, 2017. Genetics insight into the amyotrophic lateral sclerosis/frontotemporal dementia spectrum. Journal of Medical Genetics 54, 145–154. 10.1136/jmedgenet-2016-104271 [DOI] [PubMed] [Google Scholar]
  52. Ji YJ, Ugolino J, Brady NR, Hamacher-Brady A, Wang J, 2017. Systemic deregulation of autophagy upon loss of ALS- and FTD-linked C9orf72. Autophagy 13, 1254–1255. 10.1080/15548627.2017.1299312 [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Jovičić A, Mertens J, Boeynaems S, Bogaert E, Chai N, Yamada SB, Paul JW, Sun S, Herdy JR, Bieri G, Kramer NJ, Gage FH, Den Bosch LV, Robberecht W, Gitler AD, 2015. Modifiers of C9orf72 DPR toxicity implicate nucleocytoplasmic transport impairments in c9FTD/ALS. Nat Neurosci 18, 1226–1229. 10.1038/nn.4085 [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Kanekura K, Yagi T, Cammack AJ, Mahadevan J, Kuroda M, Harms MB, Miller TM, Urano F, 2016. Poly-dipeptides encoded by the C9ORF72 repeats block global protein translation. Hum Mol Genet 25, 1803–1813. 10.1093/hmg/ddw052 [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Kearse MG, Green KM, Krans A, Rodriguez CM, Linsalata AE, Goldstrohm AC, Todd PK, 2016. CGG Repeat-Associated Non-AUG Translation Utilizes a Cap-Dependent Scanning Mechanism of Initiation to Produce Toxic Proteins. Molecular Cell 62, 314–322. 10.1016/j.molcel.2016.02.034 [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Kedersha N, Chen S, Gilks N, Li W, Miller IJ, Stahl J, Anderson P, 2002. Evidence That Ternary Complex (eIF2-GTP-tRNAiMet)–Deficient Preinitiation Complexes Are Core Constituents of Mammalian Stress Granules. Mol Biol Cell 13, 195–210. 10.1091/mbc.01-05-0221 [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Khan MA, Goss DJ, 2012. Poly(A)-binding protein increases the binding affinity and kinetic rates of interaction of viral protein linked to genome with translation initiation factors eIFiso4F and eIFiso4F·4B complex. Biochemistry 51, 1388–1395. 10.1021/bi201929h [DOI] [PubMed] [Google Scholar]
  58. Knopman DS, Roberts RO, 2011. Estimating the Number of Persons with Frontotemporal Lobar Degeneration in the US Population. Journal of molecular neuroscience : MN 45, 330 10.1007/s12031-011-9538-y [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Komar AA, Hatzoglou M, 2011. Cellular IRES-mediated translation: The war of ITAFs in pathophysiological states. Cell Cycle 10, 229–240. 10.4161/cc.10.2.14472 [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Koppers M, Blokhuis AM, Westeneng H, Terpstra ML, Zundel CAC, Vieira de Sá R, Schellevis RD, Waite AJ, Blake DJ, Veldink JH, van den Berg LH, Pasterkamp RJ, 2015. C9orf72 ablation in mice does not cause motor neuron degeneration or motor deficits. Ann Neurol 78, 426–438. 10.1002/ana.24453 [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Kumar V, Hasan GM, Hassan MI, 2017. Unraveling the Role of RNA Mediated Toxicity of C9orf72 Repeats in C9-FTD/ALS. Front. Neurosci 11 10.3389/fnins.2017.00711 [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Kwon I, Xiang S, Kato M, Wu L, Theodoropoulos P, Wang T, Kim J, Yun J, Xie Y, McKnight SL, 2014. Poly-dipeptides encoded by the C9orf72 repeats bind nucleoli, impede RNA biogenesis, and kill cells. Science 345, 1139–1145. 10.1126/science.1254917 [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Lagier-Tourenne C, Baughn M, Rigo F, Sun S, Liu P, Li H-R, Jiang J, Watt AT, Chun S, Katz M, Qiu J, Sun Y, Ling S-C, Zhu Q, Polymenidou M, Drenner K, Artates JW, McAlonis-Downes M, Markmiller S, Hutt KR, Pizzo DP, Cady J, Harms MB, Baloh RH, Vandenberg SR, Yeo GW, Fu X-D, Bennett CF, Cleveland DW, Ravits J, 2013. Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration. Proc Natl Acad Sci U S A 110, E4530–E4539. 10.1073/pnas.1318835110 [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Lee K-H, Zhang P, Kim HJ, Mitrea DM, Sarkar M, Freibaum BD, Cika J, Coughlin M, Messing J, Molliex A, Maxwell BA, Kim NC, Temirov J, Moore J, Kolaitis R-M, Shaw TI, Bai B, Peng J, Kriwacki RW, Taylor JP, 2016. C9orf72 Dipeptide Repeats Impair the Assembly, Dynamics, and Function of Membrane-Less Organelles. Cell 167, 774–788. e17 10.1016/j.cell.2016.10.002 [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Lehmer C, Oeckl P, Weishaupt JH, Volk AE, Diehl-Schmid J, Schroeter ML, Lauer M, Kornhuber J, Levin J, Fassbender K, Landwehrmeyer B, Degeneration GC for FL, Schludi MH, Arzberger T, Kremmer E, Flatley A, Feederle R, Steinacker P, Weydt P, Ludolph AC, Edbauer D, Otto M, 2017. Poly-GP in cerebrospinal fluid links C9orf72-associated dipeptide repeat expression to the asymptomatic phase of ALS/FTD. EMBO Molecular Medicine 9, 859–868. 10.15252/emmm.201607486 [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Leppek K, Das R, Barna M, 2018. Functional 5′ UTR mRNA structures in eukaryotic translation regulation and how to find them. Nat Rev Mol Cell Biol 19, 158–174. 10.1038/nrm.2017.103 [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Levine TP, Daniels RD, Gatta AT, Wong LH, Hayes MJ, 2013. The product of C9orf72, a gene strongly implicated in neurodegeneration, is structurally related to DENN Rab-GEFs. Bioinformatics 29, 499–503. 10.1093/bioinformatics/bts725 [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Liu EY, Russ J, Wu K, Neal D, Suh E, McNally AG, Irwin DJ, Van Deerlin VM, Lee EB, 2014. C9orf72 hypermethylation protects against repeat expansion-associated pathology in ALS/FTD. Acta Neuropathologica 128, 525–541. 10.1007/s00401-014-1286-y [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Logroscino G, Piccininni M, 2019. Amyotrophic Lateral Sclerosis Descriptive Epidemiology: The Origin of Geographic Difference. NED 52, 93–103. 10.1159/000493386 [DOI] [PubMed] [Google Scholar]
  70. Mackenzie IR, Arzberger T, Kremmer E, Troost D, Lorenzl S, Mori K, Weng S-M, Haass C, Kretzschmar HA, Edbauer D, Neumann M, 2013. Dipeptide repeat protein pathology in C9ORF72 mutation cases: clinico-pathological correlations. Acta Neuropathol 126, 859–879. 10.1007/s00401-013-1181-y [DOI] [PubMed] [Google Scholar]
  71. Mackenzie IRA, Frick P, Grässer FA, Gendron TF, Petrucelli L, Cashman NR, Edbauer D, Kremmer E, Prudlo J, Troost D, Neumann M, 2015. Quantitative analysis and clinico-pathological correlations of different dipeptide repeat protein pathologies in C9ORF72 mutation carriers. Acta Neuropathol 130, 845–861. 10.1007/s00401-015-1476-2 [DOI] [PubMed] [Google Scholar]
  72. Maizels N, 2015. G4-associated human diseases. EMBO reports 16, 910–922. 10.15252/embr.201540607 [DOI] [PMC free article] [PubMed] [Google Scholar]
  73. Mann DM, Rollinson S, Robinson A, Bennion Callister J, Thompson JC, Snowden JS, Gendron T, Petrucelli L, Masuda-Suzukake M, Hasegawa M, Davidson Y, Pickering-Brown S, 2013. Dipeptide repeat proteins are present in the p62 positive inclusions in patients with frontotemporal lobar degeneration and motor neurone disease associated with expansions in C9ORF72. Acta Neuropathol Commun 1, 68 10.1186/2051-5960-1-68 [DOI] [PMC free article] [PubMed] [Google Scholar]
  74. Marygold SJ, Attrill H, Lasko P, 2017. The translation factors of Drosophila melanogaster. Fly 11, 65–74. 10.1080/19336934.2016.1220464 [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. May S, Hornburg D, Schludi MH, Arzberger T, Rentzsch K, Schwenk BM, Grässer FA, Mori K, Kremmer E, Banzhaf-Strathmann J, Mann M, Meissner F, Edbauer D, 2014. C9orf72 FTLD/ALS-associated Gly-Ala dipeptide repeat proteins cause neuronal toxicity and Uncll9 sequestration. Acta Neuropathol 128, 485–503. 10.1007/s00401-014-1329-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
  76. McMillan CT, Russ J, Wood EM, Irwin DJ, Grossman M, McCluskey L, Elman L, Van Deerlin V, Lee EB, 2015. C9orf72 promoter hypermethylation is neuroprotective: Neuroimaging and neuropathologic evidence. Neurology 84, 1622–1630. 10.1212/WNL.0000000000001495 [DOI] [PMC free article] [PubMed] [Google Scholar]
  77. Mizielinska S, Gronke S, Niccoli T, Ridler CE, Clayton EL, Devoy A, Moens T, Norona FE, Woollacott IOC, Pietrzyk J, Cleverley K, Nicoll AJ, Pickering-Brown S, Dols J, Cabecinha M, Hendrich O, Fratta P, Fisher EMC, Partridge L, Isaacs AM, 2014. C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins. Science 345, 1192–1194. 10.1126/science.1256800 [DOI] [PMC free article] [PubMed] [Google Scholar]
  78. Mizielinska S, Lashley T, Norona FE, Clayton EL, Ridler CE, Fratta P, Isaacs AM, 2013. C9orf72 frontotemporal lobar degeneration is characterised by frequent neuronal sense and antisense RNAfoci. Acta Neuropathol 126, 845–857. 10.1007/s00401-013-1200-z [DOI] [PMC free article] [PubMed] [Google Scholar]
  79. Mizielinska S, Ridler CE, Balendra R, Thoeng A, Woodling NS, Grässer FA, Plagnol V, Lashley T, Partridge L, Isaacs AM, 2017. Bidirectional nucleolar dysfunction in C9orf72 frontotemporal lobar degeneration. Acta Neuropathologica Communications 5, 29 10.1186/s40478-017-0432-x [DOI] [PMC free article] [PubMed] [Google Scholar]
  80. Mokas S, Mills JR, Garreau C, Fournier M-J, Robert F, Arya P, Kaufman RJ, Pelletier J, Mazroui R, 2009. Uncoupling Stress Granule Assembly and Translation Initiation Inhibition. Mol Biol Cell 20, 2673–2683. 10.1091/mbc.E08-10-1061 [DOI] [PMC free article] [PubMed] [Google Scholar]
  81. Moon SL, Sonenberg N, Parker R, 2018. Neuronal Regulation of eIF2α Function in Health and Neurological Disorders. Trends in Molecular Medicine 24, 575–589. 10.1016/j.molmed.2018.04.001 [DOI] [PubMed] [Google Scholar]
  82. Mori K, Arzberger T, Grässer FA, Gijselinck I, May S, Rentzsch K, Weng S-M, Schludi MH, Zee J van der, Cruts M, Broeckhoven CV, Kremmer E, Kretzschmar HA, Haass C, Edbauer D, 2013a. Bidirectional transcripts of the expanded C9orf72 hexanucleotide repeat are translated into aggregating dipeptide repeat proteins. Acta Neuropathol 126, 881–893. 10.1007/s00401-013-1189-3 [DOI] [PubMed] [Google Scholar]
  83. Mori K, Weng S-M, Arzberger T, May S, Rentzsch K, Kremmer E, Schmid B, Kretzschmar HA, Cruts M, Van Broeckhoven C, Haass C, Edbauer D, 2013b. The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science 339, 1335–1338. 10.1126/science.1232927 [DOI] [PubMed] [Google Scholar]
  84. Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, McCluskey LF, Miller BL, Masliah E, Mackenzie IR, Feldman H, Feiden W, Kretzschmar HA, Trojanowski JQ, Lee VM-Y, 2006. Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis. Science 314, 130–133. 10.1126/science.1134108 [DOI] [PubMed] [Google Scholar]
  85. Nguyen L, Cleary JD, Ranum LPW, 2019. Repeat-Associated Non-ATG Translation: Molecular Mechanisms and Contribution to Neurological Disease. Annual Review of Neuroscience 42 10.1146/annurev-neuro-070918-050405 [DOI] [PMC free article] [PubMed] [Google Scholar]
  86. Niblock M, Smith BN, Lee Y-B, Sardone V, Topp S, Troakes C, Al-Sarraj S, Leblond CS, Dion PA, Rouleau GA, Shaw CE, Gallo J-M, 2016. Retention of hexanucleotide repeat-containing intron in C9orf72 mRNA: implications for the pathogenesis of ALS/FTD. Acta Neuropathol Commun 4 10.1186/s40478-016-0289-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
  87. Nielsen KH, Behrens MA, He Y, Oliveira CLP, Sottrup Jensen L, Hoffmann SV, Pedersen JS, Andersen GR, 2011. Synergistic activation of eIF4A by eIF4B and eIF4G. Nucleic Acids Research 39, 2678–2689. 10.1093/nar/gkq1206 [DOI] [PMC free article] [PubMed] [Google Scholar]
  88. Nishida K, Kuwano Y, Nishikawa T, Masuda K, Rokutan K, 2017. RNA Binding Proteins and Genome Integrity. International Journal of Molecular Sciences 18, 1341 10.3390/ijms18071341 [DOI] [PMC free article] [PubMed] [Google Scholar]
  89. O’Rourke JG, Bogdanik L, Muhammad AKMG, Gendron TF, Kim KJ, Austin A, Cady J, Liu E, Zarrow J, Grant S, Ho R, Bell S, Carmona S, Simpkinson M, Lall D, Wu K, Daughrity L, Dickson DW, Harms MB, Petrucelli L, Lee EB, Lutz CM, Baloh RH, 2015. C9orf72 BAC transgenic mice display typical pathologic features of ALS/FTD. Neuron 88, 892–901. 10.1016/j.neuron.2015.10.027 [DOI] [PMC free article] [PubMed] [Google Scholar]
  90. O’Rourke JG, Bogdanik L, Yáñez A, Lall D, Wolf AJ, Muhammad AKMG, Ho R, Carmona S, Vit JP, Zarrow J, Kim KJ, Bell S, Harms MB, Miller TM, Dangler CA, Underhill DM, Goodridge HS, Lutz CM, Baloh RH, 2016. C9orf72 is required for proper macrophage and microglial function in mice. Science 351, 1324–1329. 10.1126/science.aaf1064 [DOI] [PMC free article] [PubMed] [Google Scholar]
  91. Porta S, Kwong LK, Trojanowski JQ, Lee VM-Y, 2015. Drosha Inclusions Are New Components of Dipeptide-Repeat Protein Aggregates in FTLD-TDP and ALS C9orf72 Expansion Cases. J Neuropathol Exp Neurol 74, 380–387. 10.1097/NEN.0000000000000182 [DOI] [PMC free article] [PubMed] [Google Scholar]
  92. Pottier C, Ravenscroft TA, Sanchez-Contreras M, Rademakers R, 2016. Genetics of FTLD: overview and what else we can expect from genetic studies. J. Neurochem 138, 32–53. 10.1111/jnc.13622 [DOI] [PubMed] [Google Scholar]
  93. Prasad A, Bharathi V, Sivalingam V, Girdhar A, Patel BK, 2019. Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis. Front. Mol. Neurosci 12 10.3389/fnmol.2019.00025 [DOI] [PMC free article] [PubMed] [Google Scholar]
  94. Raffaele F, Claudia M, John H, 2019. Genetics and molecular mechanisms of frontotemporal lobar degeneration: an update and future avenues. Neurobiology of Aging 78, 98–110. 10.1016/j.neurobiolaging.2019.02.006., [DOI] [PubMed] [Google Scholar]
  95. Renton AE, Majounie E, Waite A, Simón-Sánchez J, Rollinson S, Gibbs JR, Schymick JC, Laaksovirta H, van Swieten JC, Myllykangas L, Kalimo H, Paetau A, Abramzon Y, Remes AM, Kaganovich A, Scholz SW, Duckworth J, Ding J, Harmer DW, Hernandez DG, Johnson JO, Mok K, Ryten M, Trabzuni D, Guerreiro RJ, Orrell RW, Neal J, Murray A, Pearson J, Jansen IE, Sondervan D, Seelaar H, Blake D, Young K, Halliwell N, Callister J, Toulson G, Richardson A, Gerhard A, Snowden J, Mann D, Neary D, Nalls MA, Peuralinna T, Jansson L, Isoviita V-M, Kaivorinne A-L, Hölttä-Vuori M, Ikonen E, Sulkava R, Benatar M, Wuu J, Chiò A, Restagno G, Borghero G, Sabatelli M, Heckerman D, Rogaeva E, Zinman L, Rothstein J, Sendtner M, Drepper C, Eichler EE, Alkan C, Abdullaev Z, Pack SD, Dutra A, Pak E, Hardy J, Singleton A, Williams NM, Heutink P, Pickering-Brown S, Morris HR, Tienari PJ, Traynor BJ, 2011. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72, 257–268. 10.1016/j.neuron.2011.09.010 [DOI] [PMC free article] [PubMed] [Google Scholar]
  96. Rogers GW, Richter NJ, Lima WF, Merrick WC, 2001. Modulation of the Helicase Activity of eIF4A by eIF4B, eIF4H, and eIF4F. J. Biol. Chem 276, 30914–30922. 10.1074/jbc.M100157200 [DOI] [PubMed] [Google Scholar]
  97. Rossi S, Serrano A, Gerbino V, Giorgi A, Francesco LD, Nencini M, Bozzo F, Schininà ME, Bagni C, Cestra G, Carrì MT, Achsel T, Cozzolino M, 2015. Nuclear accumulation of mRNAs underlies G4C2-repeat-induced translational repression in a cellular model of C9orf72 ALS. J Cell Sci 128, 1787–1799. 10.1242/jcs.165332 [DOI] [PubMed] [Google Scholar]
  98. Rozovsky N, Butterworth AC, Moore MJ, 2008. Interactions between eIF4AI and its accessory factors eIF4B and eIF4H. RNA 14, 2136–2148. 10.1261/rna.1049608 [DOI] [PMC free article] [PubMed] [Google Scholar]
  99. Russ J, Liu EY, Wu K, Neal D, Suh E, Irwin DJ, McMillan CT, Harms MB, Cairns NJ, Wood EM, Xie SX, Elman L, McCluskey L, Grossman M, Van Deerlin VM, Lee EB, 2015. Hypermethylation of repeat expanded C9orf72 is a clinical and molecular disease modifier. Acta Neuropathologica 129, 39–52. 10.1007/s00401-014-1365-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
  100. Saberi S, Stauffer JE, Jiang J, Garcia SD, Taylor AE, Schulte D, Ohkubo T, Schloffman CL, Maldonado M, Baughn M, Rodriguez MJ, Pizzo D, Cleveland D, Ravits J, 2018. Sense-encoded poly-GR dipeptide repeat proteins correlate to neurodegeneration and uniquely co-localize with TDP-43 in dendrites of repeat-expanded C9orf72 amyotrophic lateral sclerosis. Acta Neuropathol 135, 459–474. 10.1007/s00401-017-1793-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
  101. Sakae N, Bieniek KF, Zhang Y-J, Ross K, Gendron TF, Murray ME, Rademakers R, Petrucelli L, Dickson DW, 2018. Poly-GR dipeptide repeat polymers correlate with neurodegeneration and Clinicopathological subtypes in C9ORF72-related brain disease. Acta Neuropathologica Communications 6, 63 10.1186/s40478-018-0564-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
  102. Satoh J, Yamamoto Y, Kitano S, Takitani M, Asahina N, Kino Y, 2014. Molecular Network Analysis Suggests a Logical Hypothesis for the Pathological Role of C9orf72 in Amyotrophic Lateral Sclerosis/Frontotemporal Dementia. J Cent Nerv Syst Dis 6, 69–78. 10.4137/JCNSD.S18103 [DOI] [PMC free article] [PubMed] [Google Scholar]
  103. Schludi MH, May S, Grässer FA, Rentzsch K, Kremmer E, Küpper C, Klopstock T, Arzberger T, Edbauer D, 2015. Distribution of dipeptide repeat proteins in cellular models and C9orf72 mutation cases suggests link to transcriptional silencing. Acta Neuropathol 130, 537–555. 10.1007/s00401-015-1450-z [DOI] [PMC free article] [PubMed] [Google Scholar]
  104. Sellier C, Campanari M-L, Corbier CJ, Gaucherot A, Kolb-Cheynel I, Oulad-Abdelghani M, Ruffenach F, Page A, Ciura S, Kabashi E, Charlet-Berguerand N, 2016. Loss of C9ORF72 impairs autophagy and synergizes with polyQ Ataxin-2 to induce motor neuron dysfunction and cell death. The EMBO Journal 35, 1276–1297. 10.15252/embj.201593350 [DOI] [PMC free article] [PubMed] [Google Scholar]
  105. Seltman RE, Matthews BR, 2012. Frontotemporal Lobar Degeneration: Epidemiology, Pathology, Diagnosis and Management. CNS Drugs 26, 841–870. 10.2165/11640070-000000000-00000 [DOI] [PubMed] [Google Scholar]
  106. Sen ND, Zhou F, Harris MS, Ingolia NT, Hinnebusch AG, 2016. eIF4B stimulates translation of long mRNAs with structured 5′ UTRs and low closed-loop potential but weak dependence on eIF4G. Proc Natl Acad Sci U S A 113, 10464–10472. 10.1073/pnas.1612398113 [DOI] [PMC free article] [PubMed] [Google Scholar]
  107. Sharma SD, Kraft JJ, Miller WA, Goss DJ, 2015. Recruitment of the 40S Ribosome Subunit to the 3′-Untranslated Region (UTR) of a Viral mRNA, via the eIF4 Complex, Facilitates Cap-independent Translation. J. Biol. Chem 290, 11268–11281. 10.1074/jbc.M115.645002 [DOI] [PMC free article] [PubMed] [Google Scholar]
  108. Shatsky IN, Terenin IM, Smirnova VV, Andreev DE, 2018. Cap-Independent Translation: What’s in a Name? Trends in Biochemical Sciences. 10.1016/j.tibs.2018.04.011 [DOI] [PubMed] [Google Scholar]
  109. Shi Y, Lin S, Staats KA, Li Y, Chang W-H, Hung S-T, Hendricks E, Linares GR, Wang Y, Son EY, Wen X, Kisler K, Wilkinson B, Menendez L, Sugawara T, Woolwine P, Huang M, Cowan MJ, Ge B, Koutsodendris N, Sandor KP, Komberg J, Vangoor VR, Senthilkumar K, Hennes V, Seah C, Nelson AR, Cheng T-Y, Lee S-JJ, August PR, Chen JA, Wisniewski N, Hanson-Smith V, Belgard TG, Zhang A, Coba M, Grunseich C, Ward ME, Berg LH, van den, Pasterkamp RJ, Trotti D, Zlokovic BV, Ichida JK, 2018. Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons. Nature Medicine, 10.1038/nm.4490 [DOI] [PMC free article] [PubMed] [Google Scholar]
  110. Sieben A, Van Langenhove T, Engelborghs S, Martin J-J, Boon P, Cras P, De Deyn P-P, Santens P, Van Broeckhoven C, Cruts M, 2012. The genetics and neuropathology of frontotemporal lobar degeneration. Acta Neuropathol 124, 353–372. 10.1007/s00401-012-1029-x [DOI] [PMC free article] [PubMed] [Google Scholar]
  111. Simone R, Balendra R, Moens TG, Preza E, Wilson KM, Heslegrave A, Woodling NS, Niccoli T, Gilbert-Jaramillo J, Abdelkarim S, Clayton EL, Clarke M, Konrad M, Nicoll AJ, Mitchell JS, Calvo A, Chio A, Houlden H, Polke JM, Ismail MA, Stephens CE, Vo T, Farahat AA, Wilson WD, Boykin DW, Zetterberg H, Partridge L, Wray S, Parkinson G, Neidle S, Patani R, Fratta P, Isaacs AM, 2018. G-quadruplex-binding small molecules ameliorate C9orf72 FTD/ALS pathology in vitro and in vivo. EMBO Mol Med 10, 22–31. 10.15252/emmm.201707850 [DOI] [PMC free article] [PubMed] [Google Scholar]
  112. Simone R, Fratta P, Neidle S, Parkinson GN, Isaacs AM, 2015. G-quadruplexes: Emerging roles in neurodegenerative diseases and the non-coding transcriptome. FEBS Letters, Berlin Special Issue: The Biochemical Basis of Life 589, 1653–1668. 10.1016/j.febslet.2015.05.003 [DOI] [PubMed] [Google Scholar]
  113. Sobczak K, Michlewski G, Mezer M. de, Kierzek E, Krol J, Olejniczak M, Kierzek R, Krzyzosiak WJ, 2010. Structural Diversity of Triplet Repeat RNAs. J. Biol. Chem 285, 12755–12764. 10.1074/jbc.M109.078790 [DOI] [PMC free article] [PubMed] [Google Scholar]
  114. Solomon DA, Stepto A, Au WH, Adachi Y, Diaper DC, Hall R, Rekhi A, Boudi A, Tziortzouda P, Lee Y-B, Smith B, Bridi JC, Spinelli G, Dearlove J, Humphrey DM, Gallo J-M, Troakes C, Fanto M, Soller M, Rogelj B, Parsons RB, Shaw CE, Hortobágyi T, Hirth F, 2018. A feedback loop between dipeptide-repeat protein, TDP-43 and karyopherin-α mediates C9orf72-related neurodegeneration. Brain 141, 2908–2924. 10.1093/brain/awy241 [DOI] [PMC free article] [PubMed] [Google Scholar]
  115. Sonenberg N, Hinnebusch AG, 2009. Regulation of Translation Initiation in Eukaryotes: Mechanisms and Biological Targets. Cell 136, 731–745. 10.1016/j.cell.2009.01.042 [DOI] [PMC free article] [PubMed] [Google Scholar]
  116. Sonobe Y, Ghadge G, Masaki K, Sendoel A, Fuchs E, Roos RP, 2018. Translation of dipeptide repeat proteins from the C9ORF72 expanded repeat is associated with cellular stress. Neurobiology of Disease 116, 155–165. 10.1016/j.nbd.2018.05.009 [DOI] [PMC free article] [PubMed] [Google Scholar]
  117. Spirin AS, 2009. How Does a Scanning Ribosomal Particle Move along the 5′-Untranslated Region of Eukaryotic mRNA? Brownian Ratchet Model. Biochemistry 48, 10688–10692. 10.1021/bi901379a19835415 [DOI] [Google Scholar]
  118. Su Z, Zhang Y, Gendron TF, Bauer PO, Chew J, Yang W-Y, Fostvedt E, Jansen-West K, Belzil VV, Desaro P, Johnston A, Overstreet K, Oh S-Y, Todd PK, Berry JD, Cudkowicz ME, Boeve BF, Dickson D, Floeter MK, Traynor BJ, Morelli C, Ratti A, Silani V, Rademakers R, Brown RH, Rothstein JD, Boylan KB, Petrucelli L, Disney MD, 2014. Discovery of a Biomarker and Lead Small Molecules to Target r(GGGGCC)-Associated Defects in c9FTD/ALS. Neuron 83, 1043–1050. 10.1016/j.neuron.2014.07.041 [DOI] [PMC free article] [PubMed] [Google Scholar]
  119. Sudria-Lopez E, Koppers M, de Wit M, van der Meer C, Westeneng H-J, Zundel CAC, Youssef SA, Harkema L, de Bruin A, Veldink JH, van den Berg LH, Pasterkamp RJ, 2016. Full ablation of C9orf72 in mice causes immune system-related pathology and neoplastic events but no motor neuron defects. Acta Neuropathol 132, 145–147. 10.1007/s00401-016-1581-x [DOI] [PMC free article] [PubMed] [Google Scholar]
  120. Sun Y, Atas E, Lindqvist L, Sonenberg N, Pelletier J, Meller A, 2012. The eukaryotic initiation factor eIF4H facilitates loop-binding, repetitive RNA unwinding by the eIF4A DEAD-box helicase. Nucleic Acids Res 40, 6199–6207. 10.1093/nar/gks278 [DOI] [PMC free article] [PubMed] [Google Scholar]
  121. Tabet R, Schaeffer L, Freyermuth F, Jambeau M, Workman M, Lee C-Z, Lin C-C, Jiang J, Jansen-West K, Abou-Hamdan H, Desaubry L, Gendron T, Petrucelli L, Martin F, Lagier-Tourenne C, 2018. CUG initiation and frameshifting enable production of dipeptide repeat proteins from ALS/FTD C9ORF72 transcripts. Nature Communications 9, 152 10.1038/s41467-017-02643-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
  122. Tao Z, Wang H, Xia Q, Li Ke, Li Kai, Jiang X, Xu G, Wang G, Ying Z, 2015. Nucleolar stress and impaired stress granule formation contribute to C9orf72 RAN translation-induced cytotoxicity. Hum Mol Genet 24, 2426–2441. 10.1093/hmg/ddv005 [DOI] [PubMed] [Google Scholar]
  123. Terenin IM, Smirnova VV, Andreev DE, Dmitriev SE, Shatsky IN, 2017. A researcher’s guide to the galaxy of IRESs. Cell. Mol. Life Sci 74, 1431–1455. 10.1007/s00018-016-2409-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
  124. Therrien M, Rouleau GA, Dion PA, Parker JA, 2013. Deletion of C9ORF72 Results in Motor Neuron Degeneration and Stress Sensitivity in C. elegans. PLoS One 8 10.1371/journal.pone.0083450 [DOI] [PMC free article] [PubMed] [Google Scholar]
  125. Todd PK, Oh SY, Krans A, He F, Sellier C, Frazer M, Renoux AJ, Chen K, Scaglione KM, Basrur V, Elenitoba-Johnson K, Vonsattel JP, Louis ED, Sutton MA, Taylor JP, Mills RE, Charlet-Berguerand N, Paulson HL, 2013. CGG Repeat-Associated Translation Mediates Neurodegeneration in Fragile X Tremor Ataxia Syndrome. Neuron 78, 440–455. 10.1016/j.neuron.2013.03.026 [DOI] [PMC free article] [PubMed] [Google Scholar]
  126. Todd PK, Paulson HL, 2010. RNA-mediated neurodegeneration in repeat expansion disorders. Annals of Neurology 67, 291–300. 10.1002/ana.21948 [DOI] [PMC free article] [PubMed] [Google Scholar]
  127. Tran H, Almeida S, Moore J, Gendron TF, Chalasani U, Lu Y, Du X, Nickerson JA, Petrucelli L, Weng Z, Gao F-B, 2015. Differential Toxicity of Nuclear RNA Foci versus Dipeptide Repeat Proteins in a Drosophila Model of C9ORF72 FTD/ALS. Neuron 87, 1207–1214. 10.1016/j.neuron.2015.09.015 [DOI] [PMC free article] [PubMed] [Google Scholar]
  128. Treeck BV, Protter DSW, Matheny T, Khong A, Link CD, Parker R, 2018. RNA self-assembly contributes to stress granule formation and defining the stress granule transcriptome. PNAS 115, 2734–2739. 10.1073/pnas.1800038115 [DOI] [PMC free article] [PubMed] [Google Scholar]
  129. van Blitterswijk M, DeJesus-Hernandez M, Niemantsverdriet E, Murray ME, Heckman MG, Diehl NN, Brown PH, Baker MC, Finch NA, Bauer PO, Serrano G, Beach TG, Josephs KA, Knopman DS, Petersen RC, Boeve BF, Graff-Radford NR, Boylan KB, Petrucelli L, Dickson DW, Rademakers R, 2013. Associations of repeat sizes with clinical and pathological characteristics in C9ORF72 expansion carriers (Xpansize-72): a cross-sectional cohort study. Lancet Neurol 12 10.1016/S1474-4422(13)70210-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
  130. van Blitterswijk M, DeJesus-Hernandez M, Rademakers R, 2012. How do C9ORF72 repeat expansions cause ALS and FTD: can we learn from other non-coding repeat expansion disorders? Curr Opin Neurol 25, 689–700. 10.1097/WCO.0b013e32835a3efb [DOI] [PMC free article] [PubMed] [Google Scholar]
  131. van Blitterswijk M, Gendron TF, Baker MC, DeJesus-Hernandez M, Finch NA, Brown PH, Daughrity LM, Murray ME, Heckman MG, Jiang J, Lagier-Tourenne C, Edbauer D, Cleveland DW, Josephs KA, Parisi JE, Knopman DS, Petersen RC, Petrucelli L, Boeve BF, Graff-Radford NR, Boylan KB, Dickson DW, Rademakers R, 2015. Novel clinical associations with specific C9ORF72 transcripts in patients with repeat expansions in C9ORF72. Acta Neuropathol 130, 863–876. 10.1007/s00401-015-1480-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
  132. van Blitterswijk M, Mullen B, Heckman MG, Baker MC, DeJesus-Hernandez M, Brown PH, Murray ME, Hsiung G-YR, Stewart H, Karydas AM, Finger E, Kertesz A, Bigio EH, Weintraub S, Mesulam M, Hatanpaa KJ, White CL, Neumann M, Strong MJ, Beach TG, Wszolek ZK, Lippa C, Caselli R, Petrucelli L, Josephs KA, Parisi JE, Knopman DS, Petersen RC, Mackenzie IR, Seeley WW, Grinberg LT, Miller BL, Boylan KB, Graff-Radford NR, Boeve BF, Dickson DW, Rademakers R, 2014a. Ataxin-2 as potential disease modifier in C9ORF72 expansion carriers. Neurobiol Aging 35, 2421.el3–2421.el7. 10.1016/j.neurobiolaging.2014.04.016 [DOI] [PMC free article] [PubMed] [Google Scholar]
  133. van Blitterswijk M, Mullen B, Nicholson AM, Bieniek KF, Heckman MG, Baker MC, DeJesus-Hernandez M, Finch NA, Brown PH, Murray ME, Hsiung G-YR, Stewart H, Karydas AM, Finger E, Kertesz A, Bigio EH, Weintraub S, Mesulam M, Hatanpaa KJ, White CL III, Strong MJ, Beach TG, Wszolek ZK, Lippa C, Caselli R, Petrucelli L, Josephs KA, Parisi JE, Knopman DS, Petersen RC, Mackenzie IR, Seeley WW, Grinberg LT, Miller BL, Boylan KB, Graff-Radford NR, Boeve BF, Dickson DW, Rademakers R, 2014b. TMEM106B protects C9ORF72 expansion carriers against frontotemporal dementia. Acta Neuropathol 127, 397–406. 10.1007/s00401-013-1240-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
  134. Vatsavayai SC, Nana AL, Yokoyama JS, Seeley WW, 2019. C9orf72-FTD/ALS pathogenesis: evidence from human neuropathological studies. Acta Neuropathol 137, 1–26. 10.1007/s00401-018-1921-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
  135. Vatsavayai SC, Yoon SJ, Gardner RC, Gendron TF, Vargas JNS, Trujillo A, Pribadi M, Phillips JJ, Gaus SE, Hixson JD, Garcia PA, Rabinovici GD, Coppola G, Geschwind DH, Petrucelli L, Miller BL, Seeley WW, 2016. Timing and significance of pathological features in C9orf72 expansion-associated frontotemporal dementia. Brain 139, 3202–3216. 10.1093/brain/aww250 [DOI] [PMC free article] [PubMed] [Google Scholar]
  136. Vaysse C, Philippe C, Martineau Y, Quelen C, Hieblot C, Renaud C, Nicaise Y, Desquesnes A, Pannese M, Filleron T, Escourrou G, Lawson M, Rintoul RC, Delisle MB, Pyronnet S, Brousset P, Prats H, Touriol C, 2015. Key contribution of eIF4H-mediated translational control in tumor promotion. Oncotarget 6, 39924–39940. [DOI] [PMC free article] [PubMed] [Google Scholar]
  137. Waite AJ, Bäumer D, East S, Neal J, Morris HR, Ansorge O, Blake DJ, 2014. Reduced C9orf72 protein levels in frontal cortex of amyotrophic lateral sclerosis and frontotemporal degeneration brain with the C9ORF72 hexanucleotide repeat expansion. Neurobiology of Aging 35, 1779.e5–1779.el3. 10.1016/j.neurobiolaging.2014.01.016 [DOI] [PMC free article] [PubMed] [Google Scholar]
  138. Walker SE, Zhou F, Mitchell SF, Larson VS, Valasek L, Hinnebusch AG, Lorsch JR, 2013. Yeast eIF4B binds to the head of the 40S ribosomal subunit and promotes mRNA recruitment through its N-terminal and internal repeat domains. RNA 19, 191–207. 10.1261/rna.035881.112 [DOI] [PMC free article] [PubMed] [Google Scholar]
  139. Wang IX, Grunseich C, Fox J, Burdick J, Zhu Z, Ravazian N, Hafner M, Cheung VG, 2018. Human proteins that interact with RNA/DNA hybrids. Genome Res. 28, 1405–1414. 10.1101/gr.237362.118 [DOI] [PMC free article] [PubMed] [Google Scholar]
  140. Wang Z-F, Ursu A, Childs-Disney JL, Guertler R, Yang W-Y, Bernat V, Rzuczek SG, Fuerst R, Zhang Y-J, Gendron TF, Yildirim I, Dwyer BG, Rice JE, Petrucelli L, Disney MD, 2019. The Hairpin Form of r(G4C2)exp in c9ALS/FTD Is Repeat-Associated Non-ATG Translated and a Target for Bioactive Small Molecules. Cell Chemical Biology 26, 179–190.el2. 10.1016/j.chembiol.2018.10.018 [DOI] [PMC free article] [PubMed] [Google Scholar]
  141. Webster CP, Smith EF, Grierson AJ, De Vos KJ, 2016. C9orf72 plays a central role in Rab GTPase-dependent regulation of autophagy. Small GTPases 1–10. 10.1080/21541248.2016.1240495 [DOI] [PMC free article] [PubMed] [Google Scholar]
  142. Wen X, Tan W, Westergard T, Krishnamurthy K, Markandaiah SS, Shi Y, Lin S, Shneider NA, Monaghan J, Pandey UB, Pasinelli P, Ichida JK, Trotti D, 2014. Antisense Proline-Arginine RAN Dipeptides Linked to C9orf72-ALS/FTD Form Toxic Nuclear Aggregates that Initiate In Vitro and In Vivo Neuronal Death. Neuron 84, 1213–1225. 10.1016/j.neuron.2014.12.010 [DOI] [PMC free article] [PubMed] [Google Scholar]
  143. Westergard T, McAvoy K, Russell K, Wen X, Pang Y, Morris B, Pasinelli P, Trotti D, Haeusler A, 2019. Repeat-associated non-AUG translation in C9orf72-ALS/FTD is driven by neuronal excitation and stress. EMBO Molecular Medicine e9423 10.15252/emmm.201809423 [DOI] [PMC free article] [PubMed] [Google Scholar]
  144. Wolfe AL, Singh K, Zhong Y, Drewe P, Rajasekhar VK, Sanghvi VR, Mavrakis KJ, Jiang M, Roderick JE, Meulen JV der, Schatz JH, Rodrigo CM, Zhao C, Rondou P, Stanchina E de Teruya-Feldstein J, Kelliher MA, Speleman F, Porco JA, Pelletier J, Rätsch G, Wendel H-G, 2014. RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer. Nature 513, 65 10.1038/nature13485 [DOI] [PMC free article] [PubMed] [Google Scholar]
  145. Xi Z, Rainero I, Rubino E, Pinessi L, Bruni A, Maletta R, Nacmias B, Sorbi S, Galimberti D, Surace E, Zheng Y, Moreno D, Sato C, Liang Y, Zhou Y, Robertson J, Zinman L, Tartaglia M, St George Hyslop P, Rogaeva E, 2014. Hypermethylation of the CpG-island near the C9orf72 G4C2-repeat expansion in FTLD patients. 23, 5630–5637. 10.1093/hmg/ddu279 [DOI] [PubMed] [Google Scholar]
  146. Xi Z, Zinman L, Moreno D, Schymick J, Liang Y, Sato C, Zheng Y, Ghani M, Dib S, Keith J, Robertson J, Rogaeva E, 2013. Hypermethylation of the CpG island near the G4C2 repeat in ALS with a C9orf72 expansion. Am. J. Hum. Genet 92, 981–989. 10.1016/j.ajhg.2013.04.017 [DOI] [PMC free article] [PubMed] [Google Scholar]
  147. Xiao S, MacNair L, McGoldrick P, McKeever PM, McLean JR, Zhang M, Keith J, Zinman L, Rogaeva E, Robertson J, 2015. Isoform-specific antibodies reveal distinct subcellular localizations of C9orf72 in amyotrophic lateral sclerosis. Annals of Neurology 78, 568–583. 10.1002/ana.24469 [DOI] [PubMed] [Google Scholar]
  148. Yamada SB, Gendron TF, Niccoli T, Genuth NR, Grosely R, Shi Y, Glaria I, Kramer NJ, Nakayama L, Fang S, Dinger TJI, Thoeng A, Rocha G, Barna M, Puglisi JD, Partridge L, Ichida JK, Isaacs AM, Petrucelli L, Gitler AD, 2019. RPS25 is required for efficient RAN translation of C9orf72 and other neurodegenerative disease-associated nucleotide repeats. Nat Neurosci 1–6. 10.1038/s41593-019-0455-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
  149. Yamakawa M, Ito D, Honda T, Kubo K, Noda M, Nakajima K, Suzuki N, 2015. Characterization of the dipeptide repeat protein in the molecular pathogenesis of c9FTD/ALS. Hum Mol Genet 24, 1630–1645. 10.1093/hmg/ddu576 [DOI] [PubMed] [Google Scholar]
  150. Yeh T-H, Liu H-F, Li Y-W, Lu C-S, Shih H-Y, Chiu C-C, Lin S-J, Huang Y-C, Cheng Y-C, 2018. C9orf72 is essential for neurodevelopment and motility mediated by Cyclin G1. Experimental Neurology 304, 114–124. 10.1016/j.expneurol.2018.03.002 [DOI] [PubMed] [Google Scholar]
  151. Yuva-Aydemir Y, Almeida S, Gao F-B, 2018. Insights into C9ORF72-Related ALS/FTD from Drosophila and iPSC Models. Trends in Neurosciences. 10.1016/j.tins.2018.04.002 [DOI] [PMC free article] [PubMed] [Google Scholar]
  152. Zhang D, Iyer LM, He F, Aravind L, 2012. Discovery of Novel DENN Proteins: Implications for the Evolution of Eukaryotic Intracellular Membrane Structures and Human Disease. Front. Genet 3 10.3389/fgene.2012.00283 [DOI] [PMC free article] [PubMed] [Google Scholar]
  153. Zhang K, Daigle JG, Cunningham KM, Coyne AN, Ruan K, Grima JC, Bowen KE, Wadhwa H, Yang P, Rigo F, Taylor JP, Gitler AD, Rothstein JD, Lloyd TE, 2018. Stress Granule Assembly Disrupts Nucleocytoplasmic Transport. Cell 173, 958–971. el7 10.1016/j.cell.2018.03.025 [DOI] [PMC free article] [PubMed] [Google Scholar]
  154. Zhang K, Donnelly CJ, Haeusler AR, Grima JC, Machamer JB, Steinwald P, Daley EL, Miller SJ Cunningham KM, Vidensky S, Gupta S, Thomas MA, Hong I, Chiu S-L, Huganir RL, Ostrow LW, Matunis MJ, Wang J, Sattler R, Lloyd TE, Rothstein JD, 2015. The C9ORF72 repeat expansion disrupts nucleocytoplasmic transport. Nature 525, 56–61. 10.1038/nature14973 [DOI] [PMC free article] [PubMed] [Google Scholar]
  155. Zhang Y-J, Gendron TF, Ebbert MTW, O’Raw AD, Yue M, Jansen-West K, Zhang X, Prudencio M, Chew J, Cook CN, Daughrity LM, Tong J, Song Y, Pickles SR, Castanedes-Casey M, Kurti A, Rademakers R, Oskarsson B, Dickson DW, Hu W, Gitler AD, Fryer JD, Petrucelli L, 2018. Poly(GR) impairs protein translation and stress granule dynamics in C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis. Nat. Med 24, 1136–1142. 10.1038/s41591-018-0071-l [DOI] [PMC free article] [PubMed] [Google Scholar]
  156. Zhang Y-J, Gendron TF, Grima JC, Sasaguri H, Jansen-West K, Xu Y-F, Katzman RB, Gass J, Murray ME, Shinohara M, Lin W-L, Garrett A, Stankowski JN, Daughrity L, Tong J, Perkerson EA, Yue M, Chew J, Castanedes-Casey M, Kurti A, Wang ZS, Liesinger AM, Baker JD, Jiang J, Lagier-Tourenne C, Edbauer D, Cleveland DW, Rademakers R, Boylan KB, Bu G, Link CD, Dickey CA, Rothstein JD, Dickson DW, Fryer JD, Petrucelli L, 2016. C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins. Nature Neuroscience 19, 668–677. 10.1038/nn.4272 [DOI] [PMC free article] [PubMed] [Google Scholar]
  157. Zhao M, Kim JR, van Bruggen R, Park J, 2018. RNA-Binding Proteins in Amyotrophic Lateral Sclerosis. Mol Cells 41, 818–829. 10.14348/molcells.2018.0243 [DOI] [PMC free article] [PubMed] [Google Scholar]
  158. Zu T, Gibbens B, Doty NS, Gomes-Pereira M, Huguet A, Stone MD, Margolis J, Peterson M, Markowski TW, Ingram MAC, Nan Z, Forster C, Low WC, Schoser B, Somia NV, Clark HB, Schmechel S, Bitterman PB, Gourdon G, Swanson MS, Moseley M, Ranum LPW, 2011. Non-ATG-initiated translation directed by microsatellite expansions. Proc. Natl. Acad. Sci. U.S.A 108, 260–265. 10.1073/pnas.1013343108 [DOI] [PMC free article] [PubMed] [Google Scholar]
  159. Zu T, Liu Y, Bañez-Coronel M, Reid T, Pletnikova O, Lewis J, Miller TM, Harms MB, Falchook AE, Subramony SH, Ostrow LW, Rothstein JD, Troncoso JC, Ranum LPW, 2013. RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia. Proc Natl Acad Sci U S A 110, E4968–E4977. 10.1073/pnas.1315438110 [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

1
NIHMS1545266-supplement-1.pdf (196.5KB, pdf)

RESOURCES