Nonsense-mediated RNA decay in the brain: emerging modulator of neural development and disease

Abstract

Steady-state RNA levels are controlled by the balance between RNA synthesis and RNA turnover. A selective RNA turnover mechanism that has received recent attention in neurons is nonsense-mediated RNA decay (NMD). NMD has been shown to influence neural development, neural stem cell differentiation decisions, axon guidance and synaptic plasticity. In humans, NMD factor gene mutations cause some forms of intellectual disability and are associated with neurodevelopmental disorders, including schizophrenia and autism spectrum disorder. Impairments in NMD are linked to neurodegenerative disorders, including amyotrophic lateral sclerosis. We discuss these findings, their clinical implications and challenges for the future.

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Fig. 1: Nonsense-mediated RNA decay.
Fig. 2: Nonsense-mediated RNA decay-inducing features.
Fig. 3: Alternatively spliced mRNAs are often targeted by nonsense-mediated RNA decay.
Fig. 4: Nonsense-mediated RNA decay branches, regulation and neural functions.
Fig. 5: Control of protein synthesis and mRNA levels in axons by local nonsense-mediated RNA decay during axon outgrowth.
Fig. 6: Potential roles of nonsense-mediated RNA decay in suppressing neurotoxic effects of mis-spliced mRNAs.

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Acknowledgements

This work was supported by US National Institute of Health grants NS056306 (S.J.) and R01 GM111838 (M.F.W.).

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Nature Reviews Neuroscience thanks D. Silver and the other anonymous reviewers for their contribution to the peer review of this work.

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S.J. and M.F.W. researched data for the article and made substantial contributions to discussion of content and the writing, review and editing of the manuscript before submission.

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Correspondence to Samie R. Jaffrey or Miles F. Wilkinson.

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Glossary

RNA turnover

Degradation of RNAs; typically achieved through the action of specific nucleases.

RNA surveillance

The recognition and subsequent elimination of abnormal RNAs.

Dominant-negative

Mutant proteins that antagonize the function of the wild-type protein.

Transcripts

RNAs, including those coding for protein (mRNAs).

Genome-wide studies

Analyses of the majority of the genes in a genome (for example, RNA sequencing analysis determines the level of RNAs transcribed from all significantly expressed genes in the genome).

In-frame

Codons that are in the same frame as the initiator codon.

Untranslated regions

(UTRs). The regions of an mRNA upstream and downstream of the coding region (that is, the 5′ UTR is upstream of the initiator codon and the 3′ UTR is downstream of the stop codon).

Haploinsufficiency

Loss of one copy of a gene from a diploid organism.

Commissural axons

Neurites (projections from the cell body) that cross the midline of the CNS to the other side of the nervous system.

Frameshift

Insertions and deletions downstream of the initiator codon that are not a multiple of three and thus shift the reading frame (this leads to altered amino acids in the encoded protein downstream of the frameshift).

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Jaffrey, S.R., Wilkinson, M.F. Nonsense-mediated RNA decay in the brain: emerging modulator of neural development and disease. Nat Rev Neurosci 19, 715–728 (2018). https://doi.org/10.1038/s41583-018-0079-z

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