Abstract
Tens, if not hundreds, of thousands of long non-coding RNAs (lncRNAs) are transcribed from mammalian genomes, especially in the brain, wherein most exhibit region-specific and/or cell-specific expression patterns. Many lncRNAs are nuclear-localized and appear to be the products of developmental enhancers, whereas others are found in the cytoplasm, including at the synapse. Here, we describe the lncRNAs that have been shown to have roles in various aspects of brain development, synaptic function, learning, behaviour and brain disorders. Our emerging understanding indicates that lncRNAs direct many, if not most, of the regulatory transactions that give rise to the structure of the brain and modulate its functions, probably through their guidance of relatively generic effector proteins. Although they hold promise as targets for therapeutic interventions, a concerted effort will be required to characterize the structures, functions, spatial distribution and interacting partners of the lncRNAs expressed in the brain, most of which have not been studied. We suggest that the lncRNAs transcribed from genomic regions associated with human neurological traits and disorders be prioritized for analysis.
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Acknowledgements
This work was supported by UNSW Sydney (grant RG193211) and the Australian Research Council (grants DP210103233 and DP210101957). The authors thank K. Clemens (UNSW Sydney) for the helpful comments on the manuscript. Figures were created with BioRender (https://www.biorender.com).
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Contributions
S.A. and M.J.C. assembled and curated the lists of lncRNAs and their reported functions, study models, expression patterns and phenotypic effects of knockdown or ectopic expression. S.A. also drafted the figures. J.S.M. wrote the first draft of the article and managed the revisions. L.M.I. contributed to the section ‘LncRNAs in neurological disorders’. All authors edited the article and the revised versions and approved their submission.
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Competing interests
L.M.I. is the Founder and Chief Medical Officer of Celosia Therapeutics Pty Ltd.
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Nature Reviews Neuroscience thanks Yue Feng, Gerhard Schratt and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Glossary
- Antisense lncRNAs
-
RNAs that are transcribed from the strand opposite a protein-coding gene and overlap the body of the gene (in part of full) or its promoter.
- Enhancers
-
Genetic loci that activate the spatiotemporal patterns of the expression of genes in their vicinity, independent of position, orientation or (to a limited extent) distance.
- Genome editing
-
A technique that allows precise removal, replacement or addition of specific sequences in the genome, most commonly using engineered CRISPR–Cas systems.
- Genome-wide association study (GWAS) haplotype blocks
-
Genomic segments subject to limited internal recombination, allelic variants of which can be tagged by sentinel single-nucleotide polymorphisms and linked to various human complex traits and disorders in large-scale genome wide association studies.
- MicroRNAs
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Small 21–25-nt non-coding RNAs that regulate mRNA translation and half-life by recruiting the RNA-induced silencing complex.
- Non-coding RNAs
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RNAs that are not translated into protein but have functions in gene regulation.
- Proximity labelling
-
A biochemical technique that uses engineered enzymes to covalently tag proteins or RNAs near a protein of interest, enabling identification of interaction partners with spatial precision.
- Pseudogenes
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Genomic DNA sequences derived from protein-coding genes, derived by retrotransposition of processed mRNAs or segmental duplication, which lack protein-coding capacity owing to insertions, deletions or premature stop codons.
- RNA transport granules
-
Motile phase-separated condensates of RNAs and proteins that mediate long-distance RNA trafficking along axons and dendrites.
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Altaf, S., Cummins, M.J., Ittner, L.M. et al. The emerging roles of long non-coding RNAs in the nervous system. Nat. Rev. Neurosci. 26, 661–676 (2025). https://doi.org/10.1038/s41583-025-00960-z
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DOI: https://doi.org/10.1038/s41583-025-00960-z
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