Noncoding RNAs in neurodegeneration

Key Points

  • Although most of the non-coding RNA (ncRNA) species were initially dismissed as products of spurious transcription, a wide spectrum of ncRNA regulatory mechanisms is now emerging.

  • ncRNA expression in the brain is dynamically regulated in an activity-dependent and spatiotemporally controlled manner, suggesting that ncRNAs have precise regulatory roles in brain development and function.

  • The intricate transcriptional output of genomic loci may have affected human brain evolution and could possibly explain the specific vulnerability of the human brain to neurodegeneration.

  • ncRNA expression and function is perturbed in neurodegenerative disorders, and genetic variations in ncRNA networks can be associated with disease risk.

  • Understanding the mechanistic aspects of ncRNA function in the CNS and how ncRNA dysfunction may lead to neurodegenerative disorders will probably lead to the development of new diagnostic and therapeutic approaches for these diseases.

Abstract

The emerging complexity of the transcriptional landscape poses great challenges to our conventional preconceptions of how the genome regulates brain function and dysfunction. Non-protein-coding RNAs (ncRNAs) confer a high level of intricate and dynamic regulation of various molecular processes in the CNS and they have been implicated in neurodevelopment and brain ageing, as well as in synapse function and cognitive performance, in both health and disease. ncRNA-mediated processes may be involved in various aspects of the pathogenesis of neurodegenerative disorders. Understanding these events may help to develop novel diagnostic and therapeutic tools. Here, we provide an overview of the complex mechanisms that are affected by the diverse ncRNA classes that have been implicated in neurodegeneration.

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Figure 1: Abundance of annotated loci in human genome.
Figure 2: A three-dimensional transcriptional 'code' implicated in neurodegeneration.
Figure 3: Non-coding RNA mechanisms in neurodegeneration.

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Acknowledgements

E.S. receives funding from the Fonds voor Wetenschappelijk Onderzoek (FWO) and the Alzheimer's Association. B.D.S. was supported by a European Research Council (ERC) grant for his miRNA work and is supported by the FWO, KU Leuven, VIB, and a Methusalem grant from KU Leuven and the Flemish Government. He is further supported by the Opening the Future campaign of the Leuven Universiteit Fonds (LUF). The authors are grateful to C. Sala Frigerio, E. Leucci, A. Sierksma, R. Guerreiro and J. Bras for reading the manuscript and providing critical feedback.

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ncRNAs in neurodegeneration. (PDF 1841 kb)

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Glossary

Long non-coding RNAs

(lncRNAs). Non-protein-coding transcripts that are longer than 200–400 nucleotides and include multiple diverse RNA species.

Circular RNAs

(circRNAs). Covalently closed, single-stranded transcripts that are produced by the back-splicing of exons in precursor mRNAs.

microRNAs

(miRNAs). Small (20–25 nucleotides) non-protein-coding regulatory RNA molecules that are involved in post-transcriptional regulation.

Endogenous small-interfering RNAs

(endo-siRNAs). Small (21–26 nucleotides) non-protein-coding regulatory RNAs that are produced from endogenous double-stranded RNA precursors and are involved in post-transcriptional silencing.

Small nucleolar-derived RNAs

Small (17–30 nucleotides) non-protein-coding regulatory RNAs that are derived from the processing of small nucleolar RNAs and are implicated in gene silencing.

PIWI-interacting RNAs

(piRNAs). Small (26–33 nucleotides) non-protein-coding regulatory RNAs involved in epigenetic and post-transcriptional gene silencing via interaction with PIWI proteins.

Long natural antisense transcripts

(NATs). Long (200–400 nucleotides) RNA molecules that are transcribed from the opposite DNA strand; they partially overlap with the sense transcript and often regulate its transcription, splicing or stability.

Enhancer non-coding RNAs

(eRNAs). Non-protein-coding RNAs that are transcribed from enhancer DNA loci and are implicated in the regulation of gene transcription.

Convergent transcription

Simultaneous transcription proceeding in the sense and antisense orientation from two closely positioned promoters, with the RNA polymerases heading towards each other.

Frontotemporal lobar degeneration with TAR DNA-binding protein 43 (TDP43) proteinopathy

(FTLD-TDP). Frontotemporal lobar degeneration with tau-negative, ubiquitin-positive inclusions that contain TDP43.

Seed sequence

Nucleotide sequences (2–7 nucleotides) in the 5′-end of the microRNA (miRNA) sequence that are crucial for recognizing and binding to complementary sites on target mRNA 3′-untranslated regions (UTRs).

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Salta, E., De Strooper, B. Noncoding RNAs in neurodegeneration. Nat Rev Neurosci 18, 627–640 (2017). https://doi.org/10.1038/nrn.2017.90

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