From Junk to Function: LncRNAs in CNS Health and Disease

Overview

Journal Front Mol Neurosci

Specialty Molecular Biology

Date 2021 Aug 5

PMID 34349622

Citations 24

Authors

Rafaela Policarpo

Annerieke Sierksma

Bart De Strooper

Constantin dYdewalle

Affiliations

Soon will be listed here.

Abstract

Recent advances in RNA sequencing technologies helped to uncover the existence of tens of thousands of long non-coding RNAs (lncRNAs) that arise from the dark matter of the genome. These lncRNAs were originally thought to be transcriptional noise but an increasing number of studies demonstrate that these transcripts can modulate protein-coding gene expression by a wide variety of transcriptional and post-transcriptional mechanisms. The spatiotemporal regulation of lncRNA expression is particularly evident in the central nervous system, suggesting that they may directly contribute to specific brain processes, including neurogenesis and cellular homeostasis. Not surprisingly, lncRNAs are therefore gaining attention as putative novel therapeutic targets for disorders of the brain. In this review, we summarize the recent insights into the functions of lncRNAs in the brain, their role in neuronal maintenance, and their potential contribution to disease. We conclude this review by postulating how these RNA molecules can be targeted for the treatment of yet incurable neurological disorders.

Citing Articles

LncRNAs Orchestrating Neuroinflammation: A Comprehensive Review.

Esmaeili A, Yazdanpanah N, Rezaei N Cell Mol Neurobiol. 2025; 45(1):21.

PMID: 40056236 PMC: 11890384. DOI: 10.1007/s10571-025-01538-0.

The double-edged sword of lncRNAs in rheumatoid arthritis: from controlling the disease to its progress.

Liu Z, Xu H, Chen Z Clin Exp Med. 2025; 25(1):76.

PMID: 40053152 PMC: 11889058. DOI: 10.1007/s10238-025-01567-5.

Deciphering the epigenetic role of long non-coding RNAs in mood disorders: Focus on human brain studies.

Roy B, Verma A, Funahashi Y, Dwivedi Y Clin Transl Med. 2025; 15(3):e70135.

PMID: 40038891 PMC: 11879898. DOI: 10.1002/ctm2.70135.

Advancements in genetic research and RNA therapy strategies for amyotrophic lateral sclerosis (ALS): current progress and future prospects.

Ruffo P, Traynor B, Conforti F J Neurol. 2025; 272(3):233.

PMID: 40009238 PMC: 11865122. DOI: 10.1007/s00415-025-12975-8.

lncRNA PART1 improves sevoflurane-induced impairments in learning and cognitive function by regulating miR-16-5p expression and reducing neuroinflammation.

Lin Y, Yu W, Yang W, Wang N, Zhang Q, Guan Y Toxicol Res (Camb). 2025; 14(1):tfaf009.

PMID: 39872305 PMC: 11766745. DOI: 10.1093/toxres/tfaf009.

References

Wahlestedt C . Targeting long non-coding RNA to therapeutically upregulate gene expression. Nat Rev Drug Discov. 2013; 12(6):433-46. DOI: 10.1038/nrd4018. View

Wang X, Goodrich K, Gooding A, Naeem H, Archer S, Paucek R . Targeting of Polycomb Repressive Complex 2 to RNA by Short Repeats of Consecutive Guanines. Mol Cell. 2017; 65(6):1056-1067.e5. DOI: 10.1016/j.molcel.2017.02.003. View

Tak Y, Farnham P . Making sense of GWAS: using epigenomics and genome engineering to understand the functional relevance of SNPs in non-coding regions of the human genome. Epigenetics Chromatin. 2016; 8:57. PMC: 4696349. DOI: 10.1186/s13072-015-0050-4. View

Luo T, Liu P, Wang X, Li L, Zhao L, Huang J . Effect of the autism-associated lncRNA Shank2-AS on architecture and growth of neurons. J Cell Biochem. 2018; 120(2):1754-1762. DOI: 10.1002/jcb.27471. View

Gutschner T, Baas M, Diederichs S . Noncoding RNA gene silencing through genomic integration of RNA destabilizing elements using zinc finger nucleases. Genome Res. 2011; 21(11):1944-54. PMC: 3205578. DOI: 10.1101/gr.122358.111. View

Simko E, Liu H, Zhang T, Velasquez A, Teli S, Haeusler A . G-quadruplexes offer a conserved structural motif for NONO recruitment to NEAT1 architectural lncRNA. Nucleic Acids Res. 2020; 48(13):7421-7438. PMC: 7367201. DOI: 10.1093/nar/gkaa475. View

Carrieri C, Forrest A, Santoro C, Persichetti F, Carninci P, Zucchelli S . Expression analysis of the long non-coding RNA antisense to Uchl1 (AS Uchl1) during dopaminergic cells' differentiation in vitro and in neurochemical models of Parkinson's disease. Front Cell Neurosci. 2015; 9:114. PMC: 4381646. DOI: 10.3389/fncel.2015.00114. View

DeVos S, Miller T . Antisense oligonucleotides: treating neurodegeneration at the level of RNA. Neurotherapeutics. 2013; 10(3):486-97. PMC: 3701770. DOI: 10.1007/s13311-013-0194-5. View

Benn C, Sun T, Sadri-Vakili G, McFarland K, DiRocco D, Yohrling G . Huntingtin modulates transcription, occupies gene promoters in vivo, and binds directly to DNA in a polyglutamine-dependent manner. J Neurosci. 2008; 28(42):10720-33. PMC: 2586288. DOI: 10.1523/JNEUROSCI.2126-08.2008. View

10.

Ramos A, Diaz A, Nellore A, Delgado R, Park K, Gonzales-Roybal G . Integration of genome-wide approaches identifies lncRNAs of adult neural stem cells and their progeny in vivo. Cell Stem Cell. 2013; 12(5):616-28. PMC: 3662805. DOI: 10.1016/j.stem.2013.03.003. View

11.

Zhao L, Wang J, Li Y, Song T, Wu Y, Fang S . NONCODEV6: an updated database dedicated to long non-coding RNA annotation in both animals and plants. Nucleic Acids Res. 2020; 49(D1):D165-D171. PMC: 7779048. DOI: 10.1093/nar/gkaa1046. View

12.

Roberts T, Morris K, Wood M . The role of long non-coding RNAs in neurodevelopment, brain function and neurological disease. Philos Trans R Soc Lond B Biol Sci. 2014; 369(1652). PMC: 4142028. DOI: 10.1098/rstb.2013.0507. View

13.

Mattick J, Rinn J . Discovery and annotation of long noncoding RNAs. Nat Struct Mol Biol. 2015; 22(1):5-7. DOI: 10.1038/nsmb.2942. View

14.

Faghihi M, Modarresi F, Khalil A, Wood D, Sahagan B, Morgan T . Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward regulation of beta-secretase. Nat Med. 2008; 14(7):723-30. PMC: 2826895. DOI: 10.1038/nm1784. View

15.

Sarropoulos I, Marin R, Cardoso-Moreira M, Kaessmann H . Developmental dynamics of lncRNAs across mammalian organs and species. Nature. 2019; 571(7766):510-514. PMC: 6660317. DOI: 10.1038/s41586-019-1341-x. View

16.

Pedram Fatemi R, Salah-Uddin S, Modarresi F, Khoury N, Wahlestedt C, Faghihi M . Screening for Small-Molecule Modulators of Long Noncoding RNA-Protein Interactions Using AlphaScreen. J Biomol Screen. 2015; 20(9):1132-41. PMC: 4576503. DOI: 10.1177/1087057115594187. View

17.

Khalil A, Guttman M, Huarte M, Garber M, Raj A, Rivea Morales D . Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc Natl Acad Sci U S A. 2009; 106(28):11667-72. PMC: 2704857. DOI: 10.1073/pnas.0904715106. View

18.

Xu C, Sang B, Liu G, Li J, Zhang X, Liu L . SENEBLOC, a long non-coding RNA suppresses senescence via p53-dependent and independent mechanisms. Nucleic Acids Res. 2020; 48(6):3089-3102. PMC: 7102969. DOI: 10.1093/nar/gkaa063. View

19.

Smola M, Rice G, Busan S, Siegfried N, Weeks K . Selective 2'-hydroxyl acylation analyzed by primer extension and mutational profiling (SHAPE-MaP) for direct, versatile and accurate RNA structure analysis. Nat Protoc. 2015; 10(11):1643-69. PMC: 4900152. DOI: 10.1038/nprot.2015.103. View

20.

Zhu S, Li W, Liu J, Chen C, Liao Q, Xu P . Genome-scale deletion screening of human long non-coding RNAs using a paired-guide RNA CRISPR-Cas9 library. Nat Biotechnol. 2016; 34(12):1279-1286. PMC: 5592164. DOI: 10.1038/nbt.3715. View