Long non-coding RNAs with essential roles in neurodegenerative disorders

Abstract

Recently, with the advent of high-resolution and high-throughput sequencing technologies, an increasing number of long non-coding RNAs (lncRNAs) have been found to be involved in the regulation of neuronal function in the central nervous system with specific spatiotemporal patterns, across different neurodegenerative diseases. However, the underlying mechanisms of lncRNAs during neurodegeneration remain poorly understood. This review provides an overview of the current knowledge of the biology of lncRNAs and focuses on introducing the latest identified roles, regulatory mechanisms, and research status of lncRNAs in Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. Finally, this review discusses the potential values of lncRNAs as diagnostic biomarkers and therapeutic targets for neurodegenerative diseases, hoping to provide broader implications for developing effective treatments.

Introduction

Non-coding RNAs (ncRNAs) were once regarded as “junk RNA,” as they were thought to play no role in transcriptional events (Palazzo and Koonin, 2020). However, according to the Encyclopedia of DNA Elements (ENCODE), > 90% of the human genome encodes ncRNAs, and numerous studies have identified the essential roles of ncRNAs in the regulation of gene expression in the adaptation of evolution, suggesting that ncRNAs are functional RNA molecules rather than junk transcripts (Ponting et al., 2009). Long ncRNAs (lncRNAs) are defined as RNA transcripts > 200 nucleotides (nt) in length without a canonical open reading frame. Studies from Human GENCODE suggest that there are more than 19,000 lncRNAs encoded in mammalian cells, and several of these are emerging as pivotal players in many neuronal processes such as neurogenesis, differentiation, proliferation, senescence, and apoptosis in the central nervous system (Briggs et al., 2015; Liu et al., 2022; Frankish et al., 2023; Ruffo et al., 2023; Sherazi et al., 2023; Soutschek and Schratt, 2023). Over the last few decades, with the development of powerful high-throughput sequencing technologies, a growing number of lncRNAs have been identified in neurodegenerative disorders (NDs) including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), suggesting that their dysregulation could trigger the onset and pathogenesis of NDs (Ni et al., 2022).

In this review, we provide an overview of lncRNA biology, including its classification and regulatory functions. Then, we investigate the dysregulated lncRNAs in NDs and highlight recent studies on how lncRNAs are involved in NDs. Finally, we discuss the growing interest in lncRNA-based diagnostic and therapeutic strategies for NDs.

Search Strategy

An electronic search of the literatures describing basic research and clinical research of Web of Science from 1997 to 2023 was performed using the following key words: long non-coding RNAs & neurodegenerative diseases; long non-coding RNAs & Alzheimer’s disease; long non-coding RNAs & Parkinson’s disease; long non-coding RNAs & amyotrophic lateral sclerosis; long non-coding RNAs & therapeutic. The results were further screened by title and abstract, and only studies conducted on rats, mice, and nonhuman primates and in vitro studies were included. Clinical experiments and review articles were excluded.

Biology of Long Non-coding RNAs

LncRNAs are defined as RNA transcripts longer than 200 nt, and in some cases, even longer than 100,000 nt. They are predominantly transcribed by RNA polymerase II (Pol II), with a fraction also transcribed by RNA polymerase III. LncRNAs share some similarities with mRNAs, including the presence of a 7-methyl guanosine cap at the 5′-end, with or without a 3′-end polyadenylated tail, as well as undergoing alternative splicing events that generate multiple transcript isoforms (Chen et al., 2021). Unlike mRNAs, lncRNAs generally have fewer and longer exons, with an average of 2–3 exons, while mRNAs typically contain ≥ 5 exons. In addition, lncRNAs are spliced less efficiently and have weaker internal signals for splicing (Melé et al., 2017; Guo et al., 2020b). After transcription, lncRNAs can be transported from the nucleus to the cytoplasm or remain in the nucleus, which is closely related to their functions and roles. The subcellular localization of lncRNAs determines their regulatory roles in various physiological and pathological processes. When Pol II-transcribed lncRNAs are processed with weak efficiency, they are retained in the nucleus and mainly involved in the transcriptional and epigenetic regulation of pre-mRNA processing and gene expression. A portion of the lncRNAs is shuttled from the nucleus to the cytoplasm, undergoing the identical processing pathway as mRNAs. In the cytoplasm, lncRNAs mainly function to regulate the stability and degradation of mRNAs and are involved in translational events (Wu et al., 2020; Kirchhof et al., 2022). Additionally, some lncRNAs are distributed in ribosomes, exosomes, and mitochondria, where they can display various regulatory functions in biological processes (Carlevaro-Fita et al., 2016; Dong et al., 2017; Khurana et al., 2017; Li et al., 2018b; Husna et al., 2022; Kumar et al., 2023).

Classification of lncRNAs

There is a wide range in the number of lncRNA genes found in mammalian cells. Statistics from the NONCODE database (http://www.bioinfo.org/noncode/) show that there are 527,336 lncRNA transcripts across 16 different species, including 167,150 in humans and 130,558 in mice (Zhao et al., 2016; Kopp and Mendell, 2018). However, the classification and biological function of the vast majority of lncRNAs remain highly complex and controversial. Owing to their heterogeneous genomic location relative to the protein-coding position, lncRNAs can be mainly divided into six categories, namely antisense lncRNAs, intronic lncRNAs, divergent lncRNAs, intergenic lncRNAs, promoter-associated lncRNAs, and promoter upstream lncRNAs (Figure 1; Ahmadi et al., 2020).

Figure 1.

Classification of lncRNAs includes six categories.

Antisense lncRNAs: Transcribed from the antisense strand of a protein-coding gene. Intronic lncRNAs: Transcribed from within introns of protein-coding genes. Divergent lncRNAs: Transcribed in the opposite direction and facing each other from a shared promoter with a neighboring protein-coding gene. Intergenic lncRNAs: Transcribed from regions between protein-coding genes. Promoter-associated lncRNAs: Transcribed from the promoter region of a protein-coding gene. Promoter upstream lncRNAs: Transcribed from upstream of the promoter region of a protein-coding gene. Created with BioRender.com. lncRNA: Long non-coding RNA.

The classification of lncRNAs has expanded in recent years to include additional categories, reflecting the diversity of their biological functions and genomic locations. These new categories include: (i) Enhancer RNAs: transcribed from enhancer regions and involved in enhancer-promoter looping interactions to regulate gene expression (Shen et al., 2023); (ii) Small nucleolar RNAs: involved in the modification of ribosomal RNA (Koffler-Brill et al., 2023); (iii) Circular intronic RNAs: circular RNA molecules that are derived from intronic regions and involved in the regulation of splicing (Tang et al., 2021); (iv) mRNA-like intergenic transcripts (lincRNAs): long, intergenic transcripts that are similar in structure to mRNAs but do not encode proteins (AmeliMojarad and AmeliMojarad, 2023); (v) Natural antisense transcripts (NATs): transcribed from the opposite strand of protein-coding genes and involved in the regulation of their expression (Santos et al., 2022); (vi) Bidirectional lncRNAs: transcribed in the opposite direction of nearby protein-coding genes (Bhan et al., 2017); (vii) Convergent lncRNAs: transcribed from the opposite strand of nearby protein-coding genes and converge at a common termination site (Nie et al., 2021); and (viii) microRNA (miRNA) sponges: lncRNAs that act as competitive inhibitors of miRNAs, thereby regulating the expression of their target genes (Ghafouri-Fard et al., 2022). These categories are not mutually exclusive and many lncRNAs may exhibit features of more than one category (Borkiewicz et al., 2021). lncRNAs can be categorized based on their functions and mechanisms as follows: (i) Genomic imprinting: lncRNAs can regulate gene expression in a parent-of-origin specific manner, which is known as genomic imprinting; (ii) Transcriptional regulation: lncRNAs can regulate gene expression at the transcriptional level by interacting with transcription factors, chromatin-modifying enzymes, and other transcriptional regulators; (iii) Post-transcriptional regulation: lncRNAs can regulate gene expression at the post-transcriptional level by interacting with RNA-binding proteins, miRNAs, and other post-transcriptional regulators; And (iv) Translational control: lncRNAs can regulate gene expression at the translational level by interacting with translation initiation factors, ribosomes, and other translational regulators (Huang and Hu, 2021). Recent studies have suggested that dysregulated lncRNAs are involved in various diseases such as cancer, cardiovascular diseases, neurological disorders, and infectious diseases (Schmitz et al., 2016; Lozano-Vidal et al., 2019). These lncRNAs can act as either oncogenes or tumor suppressors, depending on their molecular functions and interaction with other genes and proteins. Pathogen-induced lncRNAs, on the other hand, are lncRNAs that are induced in response to viral or bacterial infections and play a role in host defense and immune response (Wang, 2018). Understanding the functions and mechanisms of disease-associated and pathogen-induced lncRNAs could provide new insights into disease pathogenesis and potential therapeutic targets (Matouk et al., 2007; Zhou et al., 2016a). In addition, genetic variants in lncRNAs can contribute to the development of various diseases including cancer, cardiovascular disease, neurological disorders, and autoimmune diseases. These variants can affect the expression, stability, and function of lncRNAs, leading to dysregulation of gene expression and contributing to disease pathogenesis (Lozano-Vidal et al., 2019; Shi et al., 2022). Therefore, understanding the roles of lncRNA variants in disease susceptibility is crucial for developing new diagnostic and therapeutic strategies for these diseases.

The evolution and conservation of lncRNAs

Compared to protein-coding genes, the majority of lncRNAs exhibit an overall lower degree of evolutionary constraint across species and display specific spatiotemporal expression and diverse subcellular localization patterns (Ponting et al., 2009; Derrien et al., 2012). It has been found that a small number of lncRNAs can encode small functional peptides, indicating that lncRNAs may also have coding functions in biological processes (Choi et al., 2019). The origin of lncRNAs is still a topic of debate. One possible explanation for the origin of lncRNAs is chromosome rearrangement, where previously separate genomic regions are brought into close proximity resulting in the formation of an ncRNA with multiple exons. Another possible explanation for the origin of lncRNAs is that they are the result of positive evolutionary selection of protein-coding genes, leading to the metamorphosis of a protein-coding gene into a functional ncRNA sequence (Kapusta et al., 2013). X-inactive specific transcript (Xist) is a typical example that can be used to explain the origin of lncRNAs, as it evolved to play a role in dosage compensation in humans (Herzing et al., 1997; Pandya-Jones et al., 2020). Several exons and the promoter region of Xist are supposed to be derived from the “debris” of the protein-coding gene Lnx3, which encodes the ligand of numb protein-X 3. However, it is still unclear whether the evolution of Xist occurred in a two-step metamorphosis or through simultaneous steps (Shevchenko et al., 2007; Elisaphenko et al., 2008).

LncRNAs exhibit weaker conservation of both sequence and genomic synteny across species than mRNAs and miRNAs. However, conservation of the lncRNA locus region can provide evidence for lncRNA orthology in evolutionarily closer species. This suggests that some lncRNAs may have important functional roles in specific biological processes, and that their conservation is maintained through natural selection (Camilleri-Robles et al., 2022). The secondary and tertiary structures of lncRNAs are often more conserved than their primary sequence, with conservation observed in regions such as promoter sequences, splice-junction motifs, and functional domains (Ponting et al., 2009; Guo et al., 2020b). Especially, lincRNAs show conserved promoter regions at levels similar to mRNAs, indicating conserved transcription across an evolutionary timeline (Washietl et al., 2014). The functional conservation of lncRNAs is crucial for cellular and neuronal biology. In the central nervous system, lncRNAs display robust brain-specific conservation in their spatiotemporal expression patterns (Zhang et al., 2017). Certain lncRNAs with critical regulatory functions in the central nervous system exhibit higher sequence constraints and more restricted expression patterns across brain development (Douka et al., 2021). Related studies have demonstrated the transcriptional dynamics map of lncRNAs with spatial, temporal, and sex-biased specificities. These lncRNAs are evolutionarily regulated, suggesting that there is a regulatory system that may contribute to central nervous system health and disease (Liu et al., 2017b; Zhang et al., 2017).

The Regulatory Roles of Long Non-coding RNAs

lncRNAs in chromatin regulation

It has been reported that certain lncRNAs exhibit inherent regulatory potential for modifying chromatin architecture and modulating chromatin organization. Numerous lncRNAs have been found to recruit chromatin modifiers in a genome-wide manner, which can activate or inhibit their effectors at specific DNA regions. Several chromatin modifiers such as CCCTC-binding factor (CTCF), polycomb repressive complex 2 (PRC2), heterogeneous nuclear ribonucleoprotein-K (hnRNP-K), and Yin Yang 1 (YY1) have the ability to mediate chromatin interactions with lncRNAs (Hsieh et al., 2022). Xist and repeat A (RepA) work together to coat the X-chromosome and enhance the recruitment of PRC2, which is responsible for the deposition of H3K27 me3 histone modification. This modification is essential for Xist to effectively silence genes on the inactive X-chromosome (Wang et al., 2021). Additionally, Xist is capable of interacting with other chromatin regulators such as YY1 or hnRNP-K to further promote gene silencing on the inactive X-chromosome (Jeon and Lee, 2011; Nakamoto et al., 2020). The trans-acting lncRNA HOX transcript antisense RNA (HOTAIR) can interact with both H3K27 me3-catalyzing PRC2 and K3K4 me2/3-catalyzing lysine-specific demethylase 1 (LSD1), thereby promoting chromosome compaction and repression of the distal HOXD genes (Jarroux et al., 2021). Through its interactions with PRC2 and LSD1, HOTAIR can establish repressive chromatin states by promoting the deposition of H3K27 me3 and removing H3K4 me2/3 on target genes. This ultimately leads to the repression of distal HOXD genes and the modulation of cellular fate decisions (Tsai et al., 2010; Portoso et al., 2017; Garbo et al., 2022). In other examples, certain lncRNAs, such as enhancer RNAs and enhancer-associated lncRNAs, have been shown to impact chromatin topology and facilitate the stabilization of DNA looping, which in turn promotes chromatin accessibility. One such lncRNA is thymocyte differentiation factor (ThymoD), which is transcribed from a super enhancer–promoter region of the BCL11b gene. ThymoD can recruit looping factors such as CTCF, thereby facilitating the formation of a loop that assembles the enhancer and promoter regions into a single-loop region. This looping configuration can enhance the transcriptional activity of BCL11b and promote thymocyte differentiation (Isoda et al., 2017; Galan et al., 2022; Lee et al., 2022). Indeed, CTCF has been shown to interact with numerous lncRNAs to regulate chromatin looping and reshape the chromatin architecture. By binding to specific DNA sequences and recruiting chromatin remodeling complexes, CTCF can facilitate the formation of chromatin loops and modulate the accessibility of regulatory elements such as enhancers and promoters. Additionally, CTCF-lncRNA interactions can influence gene expression by promoting the formation of higher-order chromatin structures that bring distant regulatory elements into closer proximity, allowing for coordinated regulation of gene expression (Ren et al., 2022; Sanidas et al., 2022). Overall, CTCF-lncRNA interactions play important roles in the organization and function of the genome.

lncRNAs in transcriptional regulation

lncRNAs serve as important transcriptional regulators in many cellular processes. There are generally two mechanisms by which lncRNAs regulate transcription. First, lncRNA transcripts can directly impact the expression of neighboring loci. They can bind to transcription sites or recruit regulators such as transcription factors and Pol II to target either cis or trans genes.

Alternatively, lncRNAs can act as “decoys” to inhibit the binding of transcriptional regulatory factors to their target genes (Statello et al., 2021). For instance, the lncRNA promoter of CDKN1A antisense DNA damage-activated RNA (PANDAR), which is transcribed from the CDKN1A promoter, can interact with the nuclear transcription factor Y subunit A (NF-YA) and scaffold attachment factor A (SAF-A), leading to the suppression of apoptotic gene activation (Figure 2A). Moreover, PANDAR and SAF-A can recruit PRC1/2 to inhibit the expression of pro-senescent genes (Pospiech et al., 2018; Zhang et al., 2020a). Xist is a well-known lncRNA that plays a crucial role in the regulation of transcription. Xist has been shown to interact with multiple proteins, including SHARP, SAF-A, and lamin B receptor, which are required for Xist-mediated transcriptional silencing. In particular, Xist directly interacts with SHARP and recruits the silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) complex, which subsequently activates histone deacetylase 3 (HDAC3). This leads to the exclusion of Pol II from the X-chromosome (Figure 2A), resulting in a transcriptionally repressive environment that is necessary for the inactivation of one of the two X chromosomes in female mammals (McHugh et al., 2015). In addition to Xist, there are other lncRNAs that can function as transcriptional regulators through different mechanisms. For example, small nucleolar RNAs can regulate gene expression through their interaction with RNA-binding proteins, while metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and nuclear paraspeckle assembly transcript 1 (NEAT1) can form distinct long-range structures by interacting with various RNA-binding proteins (Wilusz, 2016). Furthermore, some lncRNAs can function as molecular decoys to sequester miRNAs from targeting their mRNA targets. This decoy activity has been demonstrated for several lncRNAs, including some small nucleolar RNAs and MALAT1. This type of regulation can fine-tune gene expression and has been implicated in various biological processes, including cancer progression and immune response (Liu et al., 2017a; Zhang et al., 2020b, 2022; Hu et al., 2023).

Figure 2.

Transcriptional regulation by lncRNAs.

(A) lncRNAs regulate neighboring genes. Left, PANDAR acts as a decoy for NF-YA, and subsequently removes NF-YA from the promoters of the target genes to reduce apoptotic gene expression. Right, Xist recruits SHARP and SMRT, and activates HDAC3 to exclude Pol II across the X-chromosome, subsequently mediating transcriptional silencing across the X-chromosome. (B) lncRNAs directly and indirectly regulate the alternative splicing of target genes. Left, asFGFR2 recruits EZH2 and SUZ12 to the parent DNA site and triggers the enzyme KDM2a to construct a splicing chromatin tag that obstructs the binding of MRG15-PTB to exon IIIb. In other cases, HOXB-AS3 encodes a small peptide that competitively binds to hnRNPA1, preventing hnRNPA1 from binding to E10. This alternative splicing regulation can generate PKM1 and PKM2 isoforms. Created with BioRender.com. asFGFR2: Antisense transcripts of fibroblast growth factor receptor 2; EZH2: enhancer of zeste homolog 2; FGFR2: fibroblast growth factor receptor 2; HDAC3: histone deacetylase 3; hnRNP A1: heterogeneous nuclear ribonucleoprotein A1; HOXB-AS3: HOXB cluster antisense RNA 3; KDM2a: lysine demethylase 2a; lncRNA: long non-coding RNA; MRG15-PTB: MORF4-related gene on chromosome 15-polypyrimidine tract-binding protein; NF-YA: nuclear transcription factor Y subunit A; PANDAR: CDKN1A antisense DNA damage-activated RNA; PKM: pyruvate kinase; SAF-A: scaffold attachment factor A; SHARP: SMRT/HDAC1 associated repressor protein; SMRT: silencing mediator of retinoid acid and thyroid hormone receptor; SUZ12: suppressor of zeste 12; Xist: X-inactive specific transcript.

LncRNAs can also regulate gene expression by influencing alternative splicing of targeted genes. They can induce chromatin remodeling or steric inhibition that affects the expression of target genes (Statello et al., 2021). As a product of alternative splicing, lncRNAs can also directly or indirectly participate in the regulation of alternative splicing (Ouyang et al., 2022). LncRNAs regulate alternative splicing of target genes directly by forming RNA-DNA or RNA-RNA duplexes. For instance, an evolutionarily conserved nuclear antisense lncRNA of fibroblast growth factor receptors called asFGFR2, produced from the FGFR2 gene locus, can regulate FGFR2-epithelial-specific alternative splicing (Gonzalez et al., 2015). AsFGFR2 recruits enhancer of zeste homolog2 (EZH2) and suppressor of zeste 12 (SUZ12) of PRC2 to the parental DNA site, subsequently recruiting lysine demethylase 2a (KDM2a), leading to the exclusion of the chromatin adaptor complex MORF4-related gene on chromosome 15-polypyrimidine tract-binding protein (MRG15-PTB) from exon IIIb (Figure 2B). Another lncRNA, ZEB2, can form an RNA-RNA duplex with the parental RNA site in the 5′-UTR exon under the regulation of Snail1 (Galván et al., 2015; Wang et al., 2023). Indirectly, lncRNAs can regulate alternative splicing by encoding peptides or interacting with splicing factors. Although lncRNAs generally have limited coding capacity, advances in deep-sequencing technologies and bioinformatics have led to the discovery of several functional small peptides encoded by lncRNAs. For example, the lncRNA HOXB cluster antisense RNA 3 (HOXB-AS3) encodes a 53-amino acid small peptide. The HOXB-AS3 peptide, not the HOXB-AS3 lncRNA itself, blocks hnRNP A1-dependent splicing of pyruvate kinase (PKM), thereby inhibiting PKM2 generation and miR-18a processing (Figure 2B), ultimately leading to the inhibition of cleavage of PKM exon 9 (Huang et al., 2017). Splicing factors are proteins involved in the process of pre-mRNA splicing, which is an essential step in the maturation of RNA molecules. Pre-mRNA splicing is a complex process that requires the coordinated action of a large number of splicing factors, including the spliceosome complex that comprises multiple proteins and small nuclear RNA molecules. Some lncRNAs have been shown to interact with splicing factors and influence alternative splicing. For example, the lncRNA DGCR5 has been shown to interact with the splicing factor SRSF1 and promote the inclusion of exon 9 of the FAS gene, which leads to the production of a pro-apoptotic isoform of the FAS receptor. Similarly, the lncRNA MALAT1 has been shown to interact with several splicing factors, including SR proteins and hnRNPs, and promote the inclusion of exons that contain alternative splice sites (Tripathi et al., 2010; Duan et al., 2021). Overall, these findings suggest that lncRNAs can play important roles in the regulation of alternative splicing by interacting with and modulating the activity of splicing factors.

lncRNAs modulate translation

Translation is a complex process involving three stages: initiation, elongation, and termination. Each step of translation requires the participation of multiple and dynamic ribosomes, proteins, and RNAs. Recently, a growing number of studies have reported that lncRNAs efficiently regulate translation to either inhibit or promote gene expression. For example, the lncRNA growth arrest-specific 5 (GAS5) plays a critical role in regulating cell proliferation and apoptosis. It has been reported that GAS5 interacts with the eukaryotic initiation factor 4E (eIF4E), a component of the translation initiation complex, during the initiation of the translation of c-Myc (Sang et al., 2021; Patel et al., 2023). Similarly, other lncRNAs such as the small nucleolar RNA host gene 4 have also been shown to interact with eIF4E and modulate its function (Chu et al., 2021; Pourghasem et al., 2022). In addition, a number of lncRNAs can interact with ribonucleoproteins (RNPs), including hnRNP-K, FXR1, FXR2, PUF60, and SF3B3, forming an lncRNAs-RNP complex to regulate the translation efficiency (Gumireddy et al., 2013). Numerous lincRNAs such as lincRNA-p21 are activated in a p53-dependent way. lincRNA-p21 acts as a repressor through the interaction with hnRNP-K, and subsequently triggers p53-dependent apoptosis (Huarte et al., 2010). By acting as a sponge for miRNAs, some lncRNAs can act as negative or positive regulators of translation. For example, the lncRNA gastric adenocarcinoma associated, positive CD44 regulator (GAPLINC) acts as a sponge for miR-661, which can increase the expression of eEF2K, a negative regulator of eEF2 (Gu et al., 2018). Minichromosome maintenance complex component 3-associated protein antisense RNA 1 (MCM3AP-AS1) acts as a sponge for miR-15a, a negative regulator of eIF4F, and thereby facilitates the expression of eIF4F. The MCM3AP-AS1/miR-15a/eIF4F axis has been shown to play a critical role in doxorubicin response in lymphoma cells (Guo et al., 2020a).

The Role of Long Non-coding RNAs in Neurodegenerative Disorders

There is a growing body of evidence indicating that numerous lncRNAs are functionally involved in neural differentiation and function, and their associated RNA networks may influence neurodegeneration, which can lead to NDs. These NDs are characterized by a broad range of well-known hallmarks such as the formation of amyloid-β (Aβ)-enriched plaques around neurons and hyperphosphorylated tau into neurofibrillary tangles inside neurons in AD, α-synuclein-associated Lewy bodies in PD, mutant huntingtin in HD, and TAR DNA-binding domain protein 43 (TDP43) proteinopathies in ALS (Sarkar et al., 2016; Hijaz and Volpicelli-Daley, 2020; Wu and Kuo, 2020; Tamaki and Urushitani, 2022). In the following paragraphs, we discuss the current understanding of dysregulated lncRNAs in various NDs and describe the mechanisms by which they contribute to the pathogenesis of these diseases (Table 1).

Table 1.

Dysregulated lncRNAs in neurodegenerative diseases

Diseases	lncRNAs	Up- or down-regulated	Biological function	References
AD	BACE1-AS	Up	Increase the stability of BACE1 mRNA and promote Aβ1–42 synthesis	Faghihi et al., 2008
	17A	Up	Regulate the alternative splicing of GABAB2 and enhance Aβ secretion	Massone et al., 2011; Wang et al., 2019
	MAGI2-AS3	Up	Promote Aβ-induced neurotoxicity and neuroinflammation	Zhang and Wang, 2021
	51A	Up	Regulate the alternative splicing of SORL1 and increase Aβ secretion	Ciarlo et al., 2013
	NDM29	Up	Increase the γ and β secretases activity and influence Aβ secretion	Massone et al., 2012
	H19	Up	Trigger cellular apoptosis induced by Aβ25–35	Zhang et al., 2021
	BC200	Soma: up; Dendritic: down	Regulate local protein synthesis and maintain the long-term synaptic plasticity	Mus et al., 2007
	Linc00507	Up	Regulate the expression of MAPT and TTBK1	Yan et al., 2020
	SOX21-AS1	Up	Promote the Aβ1–42-induced hyperphosphorylated tau level	Xu et al., 2020
PD	NaPINK1	Up	Stabilize the expression of PINK1 splicing isoform and disrupt mitochondrial function	Costa et al., 2013
	UCHL1-AS	Down	Decrease the level of UCHL1 and disrupt ubiquitin-proteasome system	Cartier et al., 2012; Carrieri et al., 2015
	LincRNA-21	Up	Act as a sponge for miR-1277-5p and trigger cellular apoptosis and suppress cell viability	Xu et al., 2018
	UCA1	Up	Increase the α-synuclein expression	Lu et al., 2018
	MALAT1	Up	Promote α-synuclein proteostasis and apoptosis	Dong et al., 2021
	NEAT1	Up	Promote α-synuclein proteostasis and apoptosis
HD	HAR1	Down	The REST/NRSF targets the HAR1 locus and suppresses its transcription	Johnson et al., 2010
	HTT-AS_V1	Down	Negatively regulate the HTT expression
	TUG1	Up	Essential for retinal development	Ren et al., 2022
ALS	NEAT1_2	Up	Act as a scaffold for TDP43 and FUS/TLS and regulate the paraspeckle formation	Nishimoto et al., 2013

AD: Alzheimer’s disease; ALS: amyotrophic lateral sclerosis; Aβ: amyloid-β; BACE1: β-secretase enzyme 1; BACE1-AS: β-secretase enzymes-antisense; BC200: brain cytoplasmic 200; FUS/TLS: fused in sarcoma/translocated in liposarcoma; HAR1: human accelerated region-1; HD: Huntington’s disease; HTT: huntingtin; HTT-AS_V1: antisense transcript of huntingtin; lncRNA: long non-coding RNA; MAGI2-AS3: MAGI2 antisense RNA 3; MALAT1: metastasis-associated lung adenocarcinoma transcript 1; MAPT: microtube-associated protein tau; NaPINK1: antisense transcript of PINK1; NDM29: neuroblastoma differentiation marker 29; NEAT1: nuclear paraspeckle assembly transcript 1; NEAT1_2: nuclear paraspeckle assembly transcript 1 and 2; PD: Parkinson’s disease; PINK1: PTEN-induced putative kinase 1; REST/NRSF: transcriptional repressor element-1 factor/neuron restrictive silencer factor; SORL1: sorting-related receptor 1; SOX21-AS1: SRY-box transcription factor 21 antisense divergent transcript 1; TDP43: TAR DNA-binding domain protein 43; TTBK1: tau-tubulin kinase-1; TUG1: taurine-upregulated gene1; UCA1: urothelial carcinoma-associated 1; UCHL1: ubiquitin carboxy-terminal hydrolase; UCHL1-AS: antisense transcript of ubiquitin carboxy-terminal hydrolase L1.

Roles of lncRNAs in AD

AD is the most common form of dementia and neurodegeneration and is characterized by progressive cognitive decline. The majority of AD cases are sporadic and late-onset AD. To date, numerous genome-wide association studies (GWAS) have been conducted to identify the genetic determinants elucidating the comprehensive etiology of late-onset AD. Many GWAS variants of late-onset AD have been identified in non-coding regions outside of protein-coding regions, including promoters, enhancers, and non-coding RNAs, particularly lncRNAs. An increasing number of studies have reported the involvement of lncRNAs in AD, indicating a strong association between abnormal lncRNA expression and AD pathology. The processing and maturation of amyloid precursor protein into the Aβ peptides highly rely on proper cleavage by the γ and β secretase enzymes (BACE1). BACE1-AS is a natural antisense transcript from the BACE1 gene and plays an essential role in regulating Aβ content. By increasing the stability of BACE1 mRNA and preventing binding with miR-485-5p, BACE1-AS positively regulates BACE1 protein expression and promotes Aβ_1–42 synthesis, as seen in an in vitro model (Figure 3A; Faghihi et al., 2008; Zeng et al., 2019). Some miRNAs have been identified as regulators of BACE1, such as miR-374b-5p binding the 3′-UTR region of BACE1. The lncRNA MAGI2 antisense RNA 3 (MAGI2-AS3) severs as a sponger of miR-374b-5p, in both Aβ_25–35-treated SH-SY5Y and BV2 cells. Reduction of MAGI2-AS3 or overexpression of miR374b-5p can attenuate neuroinflammation in AD cell models, indicating that the MAGI2-AS3/miR374b-5p axis may provide potential biomarkers and therapeutic targets for AD (Zhang and Wang, 2021). LncRNA 17A, transcribed from the third intron of the human G-protein-coupled receptor 51 (GPR51, known as GABAB2 receptor) gene, has been found to be upregulated in the brains of AD patients compared to healthy controls (Massone et al., 2011). In SH-SY5Y cell lines as in vitro model of AD, studies have shown that lncRNA 17A regulates the processing of GABAB₂ pre-mRNA and induces an alternative splicing isoform B of GABAB₂ in AD (Tecalco-Cruz et al., 2020; Zayed et al., 2023). The GABAB₂ splicing isoform B lacks the intramembrane sequence peptide, resulting in the production of receptors without the ability to transduce GABAB-dependent intracellular signaling. In an AD cell model, upregulation of the expression of lncRNA 17A has been shown to enhance Aβ secretion, with an increase in the Aβ_1–42/Aβ_1–40 ratio, promote autophagy, induce neurodegeneration, and suppress GABAB signaling, indicating that lncRNA 17A plays a significant role in AD pathogenesis (Figure 3B; Wang et al., 2019).

Figure 3.

Regulatory lncRNAs in AD.

(A) BACE1-AS, which positively regulates BACE1 protein expression and promotes Aβ_1–42 synthesis by increasing the stability of BACE1 mRNA and preventing its binding with miR-485-5p. (B) 17A, which induces an alternative splicing isoform B of GABAB₂, leading to the generation of receptors without the ability to transduce GABAB-dependent intracellular signaling. Upregulating the expression of 17A enhances Aβ secretion, promotes autophagy, induces neurodegeneration, and suppresses GABAB signaling. (C) 51A, which promotes the alternative splicing of SORL1 and increases the generation of Aβ. (D) NDM29, which increases γ and β secretase activity to influence Aβ secretion and Aβ_1–42/Aβ_1–40 ratio. Its expression can be induced by inflammatory cytokines such as IL-1α. (E) BC200, which facilitates the regulation of protein synthesis and is involved in the maintenance of long-term synaptic plasticity. Dysregulation of BC200 may lead to synaptodendritic deterioration, causing more Aβ accumulation and neurofibrillary tangle production. Created with BioRender.com. AD: Alzheimer’s disease; Aβ: amyloid-β; APP: amyloid precursor protein; BACE1: β-secretase enzyme 1; BACE1-AS: β-secretase enzymes-antisense; BC200: brain cytoplasmic 200; IL-1α: interleukin-1α; lncRNA: long non-coding RNA; NDM29: neuroblastoma differentiation marker 29; SORL1: sorting-related receptor 1.

In AD, lncRNA 51A, which is derived from the first intron of the sorting-related receptor 1 (SORL1) gene, plays an essential role. The SORL1 protein is a neuronal apolipoprotein E receptor and is responsible for neuronal transport processes, which is a protective factor against AD given its regulation of Aβ secretion. Overexpression of lncRNA 51A promotes the alternative splicing of SORL1, leading to an increase in the generation of Aβ in SKNBE2 cells (Figure 3C; Ciarlo et al., 2013; Vardarajan et al., 2015). The expression of the long non-coding RNA neuroblastoma differentiation marker 29 (NDM29) is upregulated in the brains of AD patients. In SKNBE2 neuroblastoma cell lines, NDM29 has been shown to increase the activity of γ and β secretases, leading to altered Aβ secretion and an increase in the Aβ_1–42/Aβ_1–40 ratio. Inflammatory cytokines such as interleukin-1α can induce the expression of NDM29, suggesting that anti-inflammatory therapies may have potential in suppressing NDM29-mediated effects on Aβ (Figure 3D; Massone et al., 2012). The lncRNA H19 is a preserved lncRNA, which localizes in the nucleus and cytoplasm. Mechanical research shows that silencing the expression levels of H19 and increasing miRNA-129 can restrain apoptosis in Aβ_25–35-induced AD-like cell model, which can be effective for AD treatment (Zhang et al., 2021).

Apart from its role in Aβ secretion, the lncRNA brain cytoplasmic 200 (BC200) also exhibits regulatory functions on synapses in AD pathogenesis. Human BC200 is primarily located in the soma and dendrites of neurons, and facilitates the regulation of protein synthesis, which is essential for maintaining long-term synaptic plasticity. It has been reported that BC200 levels decrease during aging, but are upregulated in AD brain samples. These dysregulations of BC200 may be because of its mislocalization from dendrites to perikaryons, leading to synaptodendritic deterioration and further Aβ accumulation and neurofibrillary tangle production (Figure 3E; Mus et al., 2007; Li et al., 2018a). Another main hallmark of AD is tau hyperphosphorylation. linc00507 levels have shown an increase in both the brain of APP/PS1 mice and SH-SY5Y AD-like cell line model. Linc00507 can bind miR-181c-5p as competitive endogenous RNA of microtube-associated protein tau (MAPT) and tau-tubulin kinase-1 (TTBK1; Yan et al., 2020). The lncRNA SRY-box transcription factor 21 antisense divergent transcript 1 (SOX21-AS1) is associated with the development of AD. In both Aβ_1–42-treated SY5Y cell lines and SK-N-SH cell lines, silencing the expression of SOX21-AS1 can attenuate Aβ-mediated hyperphosphorylated tau levels. SOX21-AS1 can act as a sponge for miR-107, thus indicating a potential target for AD therapeutics (Xu et al., 2020).

Roles of lncRNAs in PD

PD is the second-most common ND worldwide, and is often accompanied by cognitive deficits and motor symptoms. The gross pathology of PD includes excessive loss of dopaminergic neurons, dopamine deficiency in neuronal dendrites, and the transformation of soluble α-synuclein monomers into the harmful insoluble oligomer and fibril structures. With the development of sequencing technologies, genetic research has identified several PD-associated lncRNAs and their functions in PD (Figure 4; Taghizadeh et al., 2021). PTEN-induced putative kinase 1 (PINK1) plays a crucial role in regulating mitochondrial function, dopamine release, and motor function, strongly suggesting its involvement in the pathogenesis of PD (Costa et al., 2013). NaPINK1 is a human-specific long non-coding RNA transcribed from the antisense strand of the PINK1 locus, and it has the crucial ability to stabilize the expression of the PINK1 splicing isoform. In neuroblastoma cell lines, silencing NaPINK1 results in decreased expression level of PINK1 in neurons, indicating a broader genomic strategy for regulating the PINK1 locus in PD therapeutics (Scheele et al., 2007). Another class of lncRNAs involved in brain function and PD is the ubiquitin carboxy-terminal hydrolase L1 (UCHL1) gene (Saini et al., 2021; Caritativo et al., 2023). The UCHL1 protein is highly abundant in the brain and is specifically located in dopaminergic neurons, where it is responsible for the ubiquitin-proteasome system (Cartier et al., 2012; Ham et al., 2021). The antisense strand of UCHL1 (UCHL1-AS) is responsible for the post-transcriptional and translational processing of UCHL1, increasing the protein synthesis of UCHL1. In both in vitro and in vivo PD models, the expression of lncRNA UCHL1-AS was significantly decreased. Overexpression of UCHL1 protein shows protective effects in neurons. However, this effect is abolished in PD patients, and gene polymorphisms in UCHL1-AS are highly associated with sporadic PD. Therefore, further exploration of UCHL1-AS has potential therapeutic benefit in PD (Carrieri et al., 2015).

Figure 4.

Regulatory lncRNAs in PD.

The regulatory paradigm of several lncRNAs involved in the pathogenesis of PD, including UCHL1-AS, naPINK1, lincRNA-p21, UCA1, NEAT1, and MALAT1. These lncRNAs are involved in various mechanisms contributing to PD, such as the regulation of PINK1 expression, modulation of α-synuclein proteostasis, and regulation of neuroinflammation. Created with BioRender.com. lncRNA: Long non-coding RNA; MALAT1: metastasis-associated lung adenocarcinoma transcript 1; naPINK1: antisense transcript of PINK1; NEAT1: nuclear paraspeckle assembly transcript 1; PD: Parkinson’s disease; PINK1: PTEN-induced putative kinase 1; UCA1: urothelial carcinoma-associated 1; UCHL1: ubiquitin carboxy-terminal hydrolase L1; UCHL1-AS: antisense transcript of ubiquitin carboxy-terminal hydrolase L1.

Several other lncRNAs such as lincRNA-p21 have also been reported to influence the pathogenesis of PD by regulating α-synuclein. lincRNA-p21 can act as a competing endogenous RNA for miR-1277-5p, leading to cellular apoptosis and suppressed cell viability (Xu et al., 2018). Further experiments have verified that α-synuclein is the target gene of miR-1277-5p in SH-SY5Y cells, illustrating the relationship among lincRNA-p21, miR-1277-5p, and α-synuclein in PD (Xu et al., 2018). The role of the long non-coding RNA urothelial carcinoma-associated 1 (UCA1) has been widely studied in the development of PD. Overexpression of UCA1 has been shown to significantly increase α-synuclein expression and promote the progression of a PD-like model in SH-SY5Y cells (Lu et al., 2018). It is worth noting that several well-known lncRNAs, such as MALAT1 and NEAT1, are also involved in the progression of PD. These lncRNAs are closely correlated with neuroinflammation and promote α-synuclein proteostasis (Chen et al., 2018; Liu et al., 2020; Dong et al., 2021).

Roles of lncRNAs in HD

HD is an autosomal dominant degenerative disease caused by expansion of a CAG triplet repeat in the first exon of the HTT gene. This expansion can generate mutant huntingtin protein with potential detrimental effects. The mutant huntingtin protein accumulates in the cytoplasm of neurons and causes abnormal nuclear-cytoplasmic transport of the transcriptional repressor element-1 factor/neuron restrictive silencer factor (REST/NRSF), thereby disrupting neuronal gene expression controlled by NRSF, including both coding and non-coding genes (Shimojo, 2008). Among those non-coding genes, lncRNA human accelerated region 1 (HAR1) has been reported to be significantly decreased in the striatum of HD patients (Johnson et al., 2010; Waters et al., 2021). Further mechanistic studies have revealed that REST can target specific DNA regulatory motifs of the HAR1 locus, resulting in potent transcriptional suppression of HAR1, indicating the important roles of HAR1 in HD. The natural antisense transcript of HTT (HTT-AS) is located at the repeat locus of HD and includes three exons at the poly A tail, which can be alternatively spliced into HTT-AS_V1 (exons 1 and 3, and the CAG repeat) or HTT-AS_V2 (exons 2 and 3). The expression levels of HTT-AS_V1 were found to be reduced in the frontal cortex of HD patients. In an in vitro system of cell lines, overexpression of HTT-AS_V1 can negatively regulate HTT expression, while downregulation of HTT-AS_V1 can increase the transcript level of HTT (Chung et al., 2011). These findings establish a strong connection between HTT and HD progression, linked by lncRNAs. Among the numerous HD-related lncRNAs identified by microarray data, lncRNA taurine-upregulated gene-1 (TUG1) is upregulated in the HD brain and is also highly associated with the epigenetic regulatory complex PRC2. TUG1 is necessary for retinal development and is actively involved in multiple biological functions by regulating gene transcription and translation (Johnson, 2012). However, further exploration is required to demonstrate how TUG1 functions in HD.

Roles of lncRNAs in ALS

ALS is a neurodegenerative disease characterized by the progressive degeneration of motor neurons, leading to paralysis of the limbs and respiratory failure. The accumulation of ubiquitinated protein inclusion bodies in motor neurons is a hallmark of ALS. Recent genetic research has identified up to 17 genes related to both sporadic and familial ALS, including TDP43, fused in sarcoma/translocated in liposarcoma (FUS/TLS), and the hexanucleotide GGGGCC repeat expansion in the chromosome 9 open reading frame 72 (C9ORF72). Other genes are mainly assembled into three major categories, namely RNA processing, protein trafficking and degradation, and cytoskeletal and axonal dynamics, hence indicating the genetic complexity underlying ALS (Sreedharan et al., 2008; Chew et al., 2015; van Rheenen et al., 2021). In addition to TDP43, the accumulation of misfolded SOD1 protein is also observed in some subtypes of ALS. These protein inclusions, also known as “SOD1 aggregates,” are believed to contribute to the pathogenesis of ALS by disrupting normal cellular processes and bringing about toxicity to motor neurons (Opie-Martin et al., 2022; Sawamura et al., 2022). Although TDP43, FUS/TLS, and SOD1 are commonly involved in ALS via individual pathways, recent studies have reported that aberrant aggregation of TDP43 and FUS/TLS can directly regulate the misfolding of wild-type SOD1 in both familial and sporadic ALS (Pokrishevsky et al., 2016; Jeon et al., 2019). In addition to protein-coding genes associated with ALS, there have been reports of dysregulated lncRNAs in ALS. However, the regulatory mechanisms of lncRNAs in ALS are not well understood. One previous study reported that the lncRNA NEAT1_2 was associated with ALS in the early stages of the disease. During the early pathological course of ALS, a significant increase in paraspeckle formation is noted. NEAT1_2 acts as a scaffold in the nuclei of ALS motor neurons, binding both TDP43 and FUS/TLS, which are thought to be necessary for paraspeckle formation (Nishimoto et al., 2013).

Applications of Long Non-coding RNAs

Diagnostic biomarker in ND

In NDs, the multi-level involvement of lncRNAs in pathological processes makes them potential biomarkers for diagnosis. One of the major challenges in biomarker analysis in NDs is identifying a stable, non-invasive, and early-predictable biomarker that is resistant to enzyme digestion. lncRNAs exist not only in cellular components but also in various circulating fluids such as plasma, serum, and cerebrospinal fluid, which are regarded as extracellular or circulating lncRNAs. The receiver operating characteristic curve analysis showed that the significant differences of BACE1-AS were found between pre-AD and healthy controls (75% sensitivity and 100% specificity), full-AD and healthy controls (68% sensitivity and 100% specificity), and pre-AD and full-AD subgroups (78% sensitivity and 100% specificity), indicating that BACE1-AS can be a potential biomarker for AD diagnosis (Fotuhi et al., 2019). Many dysregulated lncRNAs have been reported in HD and AD; however, there is still limited research regarding lncRNAs as biomarkers. Additionally, exosomal lncRNAs have been found to participate in the neuronal process in NDs and can be detected by simple, convenient, and inexpensive methods. The circulating lncRNA profiles in exosomes can emerge as cycling indicators of individual’s physiological status, underlying their potential as a promising biomarker for early diagnosis (Li et al., 2021).

Promising therapeutic strategies of lncRNAs in ND

To date, lncRNAs have been found to be involved in the pathogenesis of multiple NDs and have provided potential therapeutic targets for drug development. The main functions of lncRNA include transcriptional regulation, post-transcriptional regulation, and translational regulation. Based on these functions, various lncRNA-based therapeutics have been developed such as NATs, oligonucleotides, small-interfering RNAs, short hairpin RNAs, antisense oligonucleotides, and CRISPR-Cas9-based gene editing. Some of these therapeutics have already been approved by the U.S. Food and Drug Administration (FDA) and/or European Medicines Agency (EMA) (Table 2; Winkle et al., 2021; Ingle and Fang, 2023). In addition, some lncRNAs may form complex secondary structures that could be potential targets for small molecule therapeutics. Small molecules have several advantages, such as good solubility, bioavailability, and stability, which make them an ideal choice for targeting lncRNAs (Fatemi et al., 2014).

Table 2.

RNA therapeutic drug approved by FDA and/or EMA

Agent	Therapeutic drug	Disease	Mechanism of target gene	Approval agency/year
Oligonucleotides	Defibrotide	Severe hepatic veno-occlusive disease	Adenosine receptors (A1, A2a, A2b)	FDA/2016
	Mipomersen	Familial hypercholesterolemia	Apolipoprotein B mRNA	FDA/2013
	Pegaptanib	Neovascular age-related macular degeneration	Vascular endothelial growth factor 165	FDA/2004
Antisense oligonucleotides	Casimersen	Duchenne muscular dystrophy	Duchenne muscular dystrophy gene (exon 45)	FDA/2021
	Eteplirsen	Duchenne muscular dystrophy	Exclusion of exon 51 from the Duchenne muscular dystrophy mRNA	FDA/2016
	Fomivirsen	Cytomegalovirus retinitis	Cytomegalovirus IE-2 mRNA	FDA/1998
	Golodirsen	Duchenne muscular dystrophy	Dystrophin	FDA/2019
	Nusinersen	Spinal muscular atrophy	Survival motor neuron-2 protein	FDA/2016
	Inotersen	Hereditary transthyretin amyloidosis	Transthyretin mRNA	FDA/2018
	Viltolarsen	Duchenne muscular dystrophy	Duchenne muscular dystrophy gene	FDA/2020
	Volanesorsen	Familial chylomicronaemia syndrome	Apo C-III mRNA	EMA/2019
siRNAs	AMVUTTRA	Amyloidogenic transthyretin amyloidosis	Transthyretin mRNA	FDA/2022
	Givosiran	Acute hepatic porphyria	5-aminolevulinic acid synthase 1 mRNA	FDA/2019
	Inclisiran	Primary hypercholesterolemia	Inhibit hepatic translation proprotein convertase subtilisin-kexin type 9	EMA/2020
				FDA/2021
	Lumasiran	Primary hyperoxaluria type 1	Hydroxyacid oxidase-1	FDA/2020
	Patisiran	Hereditary transthyretin amyloidosis	Transthyretin mRNA	FDA/2018

Apo C-III: Apolipoprotein C-III; EMA: European Medicines Agency; FDA: U.S. Food and Drug Administration.

To decrease lncRNA expression in NDs at the RNA level, antisense oligonucleotides, small-interfering RNAs, and short hairpin RNAs are considered ideal therapeutics (Winkle et al., 2021). They all share the basic principle of binding to their target RNA loci or target pre-mRNA splicing. Some antisense oligonucleotides can target NATs, also known as “antagoNATs” and can upregulate the expression of certain lncRNAs (Ling et al., 2013; Rupaimoole and Slack, 2017). With the advancement of genome-editing tools, the CRISPR-Cas9 system presents new opportunities for targeting lncRNA genes at the DNA level. This system can be used to repress or activate gene expression through the dead Cas9 approach by fusing with the repressor (CRISPRi) or activator protein domain (CRISPRa), as well as degrading the transcripts themselves (CRISPR-Cas13) (Cox et al., 2017; Winkle et al., 2021). Several lncRNAs including BACE1-AS, 51A, 17A, and lincRNA-p21 have utilized the advantages of the CRISPR-Cas9 system for the treatment of neurological disorders. However, the application of the CRISPR-Cas9 system in vivo still faces several challenges, including off-target effects, safety concerns, immunological responses, and delivery issues. Besides the modulation of expression levels, the direct steric hindrance of structural elements or indirect effects on protein interactions by small molecules may be another viable therapeutic approach. LncRNAs have structurally conserved elements, which make them more stable and easier to be targeted by small molecules than protein targets. Small molecules can act as structural element blockers to affect the secondary or tertiary structures of lncRNAs or emerge as interaction element blockers to hide the interaction domain with its effector. Some small molecules such as NP-C86 and SEL have shown promise as potential candidates for regulating the expression of GAS5, NEAT1, and MALAT1 in NDs owing to their stability, efficacy, tolerability, and pharmacokinetic, and dynamic characteristics (Zhong et al., 2021).

To facilitate the delivery of RNA therapeutic drugs, it is essential to develop a delivery system. Although there are many delivery approaches such as physical methods (e.g., electroporation, microinjection, and hydrodynamic injection); viral vectors (e.g., lentiviral and adeno-associated viral); and nonviral carriers (e.g., nanoparticles) (Ingle and Fang, 2023), inefficient intracellular delivery, off-target effects, immunogenicity, and potential damage to cells impede their massive production and clinical application. Although challenging, some recent potentially useful solutions have provided promising delivery systems for clinical translation, including modified nanoparticles, exosome-mediated RNA delivery, and bacteriophage and bacterial minicell delivery vehicles. We believe that with ongoing research advancements, the current challenges will ultimately be overcome (Pan et al., 2012; Zhou et al., 2016b; Khoshnevisan et al., 2018).

Conclusion

In this review, we have discussed the diverse regulatory functions of lncRNAs in chromatin modification, transcription, and translation. We have also discussed the significant role of lncRNA-mediated mechanisms in the pathogenesis of NDs such as AD, PD, HD, and ALS. Although numerous genetic mutations can result in abnormal transcriptional phenotypes in NDs, our understanding of the biology and regulatory functions of lncRNAs in NDs is still limited. The biological functions of many annotated lncRNAs remain unclear. Our review shows that research on lncRNAs in ALS is still scarce. Transcriptome sequencing technologies and bioinformatic tools are essential for identifying the features of lncRNAs, including their sequence, processing, structural organization, heterogeneity of different cell subtypes, and subcellular location. More work is required to determine whether the molecular functions of lncRNAs gene expression itself are sufficient to affect the organism and trigger pathological consequences. A limitation of this review is that we have mainly only focused on the basic research of lncRNAs in NDs; clinical data or patient-oriented studies are very few. The lack of clinical trial data significantly impedes the medical translation of lncRNAs, which poses a great challenge to recognize lncRNAs as the hallmark and therapeutic target in NDs. Overall, a deeper investigation of the functions and mechanisms of aberrant lncRNAs in NDs will provide more insights into the roles of lncRNAs and potentially lead to more reliable and efficient diagnoses and therapeutics for NDs.

Funding Statement

Funding: This work was supported by the National Natural Science Foundation of China, Nos. 91649119 and 92049105 (both to JL).