Non-coding RNAs (ncRNAs) are RNA molecules that do not encode proteins but are involved in dynamic cellular regulatory processes.1 These molecules influence various central nervous system (CNS) functions, including neural development, brain aging, synaptic activity, and cognitive performance.
A clearer understanding of their role in the pathogenesis of neurodegenerative disorders could support the development of novel diagnostic and therapeutic approaches.
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ncRNAs: Types and Functions
For many years, non-coding RNAs (ncRNAs) were regarded as transcriptional by-products with limited biological significance due to their lack of protein-coding potential. However, advances in computational analysis and large-scale sequencing have expanded our understanding of the RNA landscape.
In 2005, the Human Genome Project (HGP) revealed the presence of numerous long non-coding RNAs (lncRNAs) in mammals.2 Subsequent research has shown that approximately 80 % of the human genome can be transcribed into ncRNAs.
Contrary to earlier assumptions, these molecules have been found to regulate a wide range of physiological, developmental, and disease-related processes. For example, some ncRNAs function as oncogenic drivers, while others act as tumor suppressors.
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ncRNAs operate within complex, interconnected molecular networks and influence subcellular localization. Based on their functions, they are broadly categorized into housekeeping ncRNAs and regulatory ncRNAs.3 These classifications are discussed below:
Housekeeping ncRNAs
Housekeeping ncRNAs are small RNA molecules ranging from 50 to 500 nucleotides (nt) in length. They are ubiquitously and abundantly expressed across all cell types and are essential for cellular viability. Some also contribute to regulatory functions through RNA cleavage.
Regulatory ncRNAs
Regulatory ncRNAs are involved in controlling gene expression at the epigenetic, transcriptional, and post-transcriptional levels. Based on size, they are broadly classified into small non-coding RNAs (sncRNAs) and lncRNAs.
Typically, sncRNAs are shorter than 200 nt, while lncRNAs are longer than 200 nt. Some ncRNAs with variable length, such as enhancer RNAs (eRNAs), circular RNAs (circRNAs), and promoter-associated transcripts (PATs), belong to both classifications simultaneously.
Scientists have further classified sncRNAs into microRNA (miRNA), piwi-interacting RNAs (piRNAs), and small interfering RNAs (siRNAs). Translation-interfering tRNAs (tiRNAs) and tRNA-derived RNA fragments (tRFs) are small regulatory ncRNAs derived from tRNA or pre-tRNA.
Among various sncRNA classes, miRNAs are most abundantly found and are associated with regulating gene expression in both the nucleus and cytoplasm through diverse mechanisms. Generally, at the post-transcriptional level, miRNAs induce gene silencing.
lncRNAs are further categorized based on their regulatory interactions with DNA sequences. Trans-lncRNAs (trans-acting lncRNAs) regulate genes located at distant genomic loci, while cis-lncRNAs (cis-acting lncRNAs) influence nearby gene expression.
Want to explore how lncRNAs and circRNAs regulate gene expression in greater depth?
LncRNAs, CircRNAs, and the Unseen Regulators of Gene Expression
The Role of ncRNAs in Neurodegeneration
The human brain exhibits the richest repertoire of ncRNA species. Many neurodevelopmental disorders, including Down syndrome (DS), Rett syndrome, Fragile X syndrome (FXS), and Prader-Willi Angelman syndrome, show dysregulated ncRNA expression, which impacts brain function through various mechanisms.4
Altered miRNA expression profiles have been documented across a wide range of neurodegenerative disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease (HD).5
Chromatin immunoprecipitation (ChIP) assays have revealed that lncRNA-SCA7 is involved in the pathogenesis of Spinocerebellar Ataxia type 7 (SCA7) through epigenetic regulation. SCA is a neurodegenerative disorder characterized by progressive cerebellar ataxia and pigmentary degeneration of the retina.6
Autism spectrum disorder (ASD) is a neurodevelopmental condition that affects behavior and communication. Children with ASD often experience cognitive impairment, language difficulties, and epilepsy.
In individuals with ASD, more than 200 lncRNAs were found to be differentially expressed in the prefrontal cortex and cerebellum. Pathway enrichment analysis indicated that changes in lncRNA expression influence synaptic vesicle cycling and the long-term inhibition of neural pathways.7
Both miRNAs and lncRNAs (FMR5 and FMR6) are associated with the development of FXS, which results from the inactivation or dysfunction of the FMR1 (fragile X mental retardation 1) gene. During the blastocyst stage, ncRNA expression is downregulated to promote the synthesis of fragile X mental retardation protein (FMRP), supporting normal neuronal development.
Beyond epigenetic regulation, ncRNAs also contribute to neurodegeneration by altering the splicing profiles of transcripts. For instance, alternative splicing associated with lncRNA 17A has been implicated in the pathogenesis of AD.
The role of non coding RNAs in Alzheimer's disease
Diagnostics and Therapeutics
Significant alterations in miRNA levels occur in cerebrospinal fluid (CSF) and peripheral tissues in several neurodegenerative disorders. A recent study reported elevated levels of miR-206 in the brains of AD patients, which could also be detected in the olfactory mucosa. Since miR-206 levels correlate with the degree of cognitive impairment, it may serve as a potential biomarker for early AD diagnosis.8
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects the nerve cells in the brain and spinal cord. Patients typically develop muscle weakness and atrophy, eventually leading to paralysis. Researchers have identified polyglutamine proteins in CSF and sense and antisense C9ORF72 RNA foci in fibroblasts and lymphoblasts. These ncRNA and protein species could be used as biomarkers to detect ALS.9
Given their involvement in the pathogenesis of various neurodegenerative diseases, ncRNAs are frequently targeted for therapeutic intervention. However, targeting lncRNAs is challenging due to their extensive secondary structures.
Synthetic biologists have designed oligonucleotides with multiple chemically modified analogs to overcome this challenge. In mouse models, antisense oligonucleotides (ASOs) targeting repeat-containing C9ORF72 transcripts, along with small molecules, successfully inhibited RNA translation in ALS and also led to cognitive improvements.
Inhibiting specific circular RNA (circRNA) formation has shown promise in reducing cytotoxicity and improving therapeutic outcomes in ALS. Additionally, a small interfering RNA (siRNA)–based cleavage strategy targeting natural antisense transcripts (NATs) associated with HD and AD altered both the NATs and their corresponding sense mRNAs in mouse and human cell lines, demonstrating potential therapeutic benefits.
Many pharmaceutical companies are actively exploring ncRNAs, particularly miRNAs and lncRNAs, as a potential treatment for neurological disorders. Although most are still in the optimization phase of drug development, few are being assessed in clinical phases to determine their therapeutic efficacy and safety.
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References and Further Reading
- Nemeth K, et al. et al. Non-coding RNAs in disease: from mechanisms to therapeutics. Nat Rev Genet. 2024; 25: 211–232. doi.org/10.1038/s41576-023-00662-1
- Amaral P, et al. The status of the human gene catalogue. Nature. 2023 Oct;622(7981):41-47. doi: 10.1038/s41586-023-06490-x.
- Zhang P, et al. Non-Coding RNAs and their Integrated Networks. J Integr Bioinform. 2019;16(3):20190027. doi: 10.1515/jib-2019-0027.
- Rangasamy S, et al. Epigenetics, autism spectrum, and neurodevelopmental disorders. Neurotherapeutics. 2013;10(4):742-56. doi: 10.1007/s13311-013-0227-0.
- Nguyen TPN, et al. MicroRNA Alteration, Application as Biomarkers, and Therapeutic Approaches in Neurodegenerative Diseases. International Journal of Molecular Sciences. 2022; 23(9):4718. doi.org/10.3390/ijms23094718
- Sparber P, et al. The role of long non-coding RNAs in the pathogenesis of hereditary diseases. BMC Med Genomics. 2019;12(Suppl 2):42. doi: 10.1186/s12920-019-0487-6.
- Zhang SF, et al. The Role of Non-Coding RNAs in Neurodevelopmental Disorders. Front Genet. 2019;10:1033. doi: 10.3389/fgene.2019.01033.
- Kenny A, et al. Elevated Plasma microRNA-206 Levels Predict Cognitive Decline and Progression to Dementia from Mild Cognitive Impairment. Biomolecules. 2019;9(11):734. doi: 10.3390/biom9110734.
- Ghasemi M, et al. Glial Cell Dysfunction in C9orf72-Related Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Cells. 2021; 10(2):249. doi.org/10.3390/cells10020249