Table 1.
SG assembly-related proteins in NDDs
| Names of proteins | Related NDDs | Pathogenic proteins affected | Interaction site or domain | Results | References | |
|---|---|---|---|---|---|---|
| RNA binding protein | ANXA11 | ALS | N-terminal-LCD-mutants (p.G38R, p. D40G) | The ANX domain missense variants alter SG disassembly | [86] | |
| ATXN2 | ALS/SCA | – | ATXN2-IDR | ATXN2 localizes to SGs and promotes TDP-43 mis-localization. Decreasing ATXN2 prolongs lifespan and alleviates pathology in TDP-43 mice. ATXN2 IDR drives in vivo LLPS and in vivo RNP assembly | [87, 88] | |
| G3BP1 | HD |
HTT TDP-43 |
– | The superior frontal cortex of both R6/2 mice and human HD postmortem brain tissues were found with a notable increase in G3BP1 granules | [89] | |
| SCA | ATXN2/3 | G3BP1-NTF2L | G3BP1 overexpression decreased protein aggregation | [90] | ||
| ALS-FTD | TDP-43 | – | TDP-43 is colocalized with G3BP1-positive SGs, and TDP-43 can regulate the stability of G3BP1 mRNA | [47, 91] | ||
| hnRNPA1/A2/B1 | ALS |
TDP-43 FUS |
hnRNPA2-D290 V hnRNPA1-D262 V hnRNPA1-D262 N hnRNPA1-P288 A (LCD-mutants) |
Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 promote phase separation and regulate SG dynamics | [92, 93] | |
| hnRNPA2/B1 | AD | Tau | – |
Tau oligomerization induces striking cytoplasmic translocation of m6A to co-localize with HnRNPA2/B1 and oligo Tau |
[94] | |
| FUS | ALS | – | FUS-R521C; FUS-P525L; arginine-rich RGG3 domain; FUSp−Y526 | FUS mislocalization into cytoplasmic SGs | [72, 95–97] | |
| PABP/DDX6 | AD | Tau | – | They are insoluble and colocalized with phosphorylated tau pathology | [98, 99] | |
| PABP | ALS | TDP-43 | – | PABP modulates TDP-43 toxicity. Cytoplasmic PABP is mis-localized in spinal cord motor neurons | [100] | |
| TAF15 | ALS | – | M368T, G391E, R408C, G473E | TAF15 variants showed cytoplasmic puncta formation in spinal cord neurons, and TAF15 can mislocalize into cytoplasmic SGs under cell stress | [101, 102] | |
| TDP-43 | ALS | – | TDP-43 glycine-rich LCD at the C-terminal | TDP-43 as a component of neuronal RNP transport particles, exhibits liquid-like properties. The LCD also mediates LLPS and recruitment of TDP-43 to SGs | [103] | |
| TIA1 | ALS-FTD | TDP-43 | TIA1 LCD-P362L, E384K, A381T | TIA1 mutations promote TDP-43 phase separation and alter SG dynamics, and make TDP-43 insoluble | [104, 105] | |
| AD | Tau |
TIA1 interacts with Tau’s microtubule-binding domain |
Tau phase separation is accelerated and the production of hazardous oligomeric tau is controlled by direct contact with TIA1 | [82] | ||
| Other related protein | C9orf72 | ALS-FTD | – | Hexanucleotide repeat expansions (G4C2) | Hexanucleotide repeat expansions lead to the abnormal accumulation of RNA lesions and the spontaneous formation of SGs. C9orf72 affects the clearance of SGs through interaction with eIF2α as well as autophagy receptor P62. Finally, abnormal accumulation of TDP-43 inclusion bodies is induced | [106–109] |
| Karyopherin-β1/β2 | ALS-FTD | FUS, TDP-43, hnRNPA1/A2 | PrLDs | Karyopherin-β1/β2 activates PY-NLSs to prevent and reverse the fibrillation of TDP-43, FUS, TAF15, EWSR1, hnRNPA1, and hnRNPA2, and inhibits RBP recruitment to SGs | [110] | |
| SOD1 | ALS | – |
SOD1-L144F SOD1-G93A SOD1-A4V |
Mutant SOD1 delays the formation of G3BP1- and TIA1-positive SGs by interacting with G3BP1 in an RNA-independent manner | [111] | |
| – | SOD1-G93A | TIA1 shows increased mis-localization and the interaction between SOD1 and TIA1 increases with disease progression and severity | [112] | |||
| STAU1 | SCA | ATXN2 | – | STAU1 interacts with ATXN2 and regulates SG formation | [113] | |
| Ubiquitin2 | ALS | – | – | Ubiquitin2 co-localizes with SG component proteins G3BP1, TIA1, ATXN2, and PABPC1. Ubiquitin2 mutation affects the assembly of SGs by regulating TIA1 | [40] | |
| USP10 | ALS | TDP-43 | – | By boosting clearance of SGs and aggregate formations, USP10 prevents formation of aberrant TDP-43/TDP-35 aggregates in SG in neuronal cells | [81] | |
| AD | Tau |
USP10 (1–274) USP10 (275–798) |
USP10 overexpression induces TIA1/Tau/USP10-triple-positive SGs | [114] | ||
| VCP | ALS/AD/FTD | – | – | Reduced VCP impairs SG assembly and disassembly | [115, 116] | |
| Eukaryotic translation initiation factor | eIF2α | NDDs | – | – | eIF2α phosphorylation inhibits translation initiation complex formation and promotes SG formation | [22] |
| AD | Tau | – | eIF2α is co-localized with phosphorylated tau | [98] | ||
| ALS | TDP-43 | SGs and translation-inhibiting eIF2α phosphorylation become abnormally upregulated on TDP-43 toxicity in Drosophila | [100] | |||
| eIF3η | ALS | – | – | As a eukaryotic translation initiation factor as well as a marker of SGs, it can localize to mislocalized pathogenic proteins | [96] |
AD, Alzheimer's disease; ALS, amyotrophic lateral sclerosis; ANXA11, annexin A11; ATXNT2, ataxin-2; C9orf72, Open Reading Frame 72 on chromosome 9; DDX6, DEAD-box helicase 6; eIF2α, eukaryotic translation initiation factor 2α; eIF3η, eukaryotic translation initiation factor 3η;EWSR1, Ewing’s sarcoma protein R1; FTD, frontotemporal dementia; FUS, fused in sarcoma; G3BP1, Ras-GAP SH3-domain-binding protein 1; HD, Huntington’s disease; hnRNPA1, heterogeneous nuclear ribonucleoprotein A1; hnRNPA2/B1, heterogeneous nuclear ribonucleoprotein; HTT, huntingtin protein; IDR, intrinsically disordered region; LCD, low complexity domain; m6A, N6-methyladenosine; MTBD, microtubule binding domain; NDDs, neurodegenerative diseases; NTF2L, nuclear transport factor 2-like; PABP, poly(A)-binding protein; PrLDs, Prion-like Domains; PY-NLS, PY-Nuclear localization signals; RGG, arginine‐glycine‐glycine repeat; RBPs, RNA binding proteins; SCA, spinocerebellar ataxia; SGs, stress granules; SOD1, superoxide dismutase 1; TDP-35, TAR DNA binding protein 35; TDP-43, TAR DNA binding protein 43; TAF15, TATA-box binding protein associated factor 15; tau-P2, proline-rich region P2; TIA1, T cell-restricted intracellular antigen-1; USP10, ubiquitin-specific peptidase 10; VCP, valosin-containing protein