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Brain Res. 2018 Aug 15;1693(Pt A):67-74. doi: 10.1016/j.brainres.2018.01.015. Epub 2018 Jan 31.

TDP43 and RNA instability in amyotrophic lateral sclerosis.

Author information

1
Neuroscience Graduate Program and Department of Neurology, University of Michigan School of Medicine, Ann Arbor, MI, United States.
2
Neuroscience Graduate Program and Department of Neurology, University of Michigan School of Medicine, Ann Arbor, MI, United States. Electronic address: sbarmada@umich.edu.

Abstract

The nuclear RNA-binding protein TDP43 is integrally involved in RNA processing. In accord with this central function, TDP43 levels are tightly regulated through a negative feedback loop, in which TDP43 recognizes its own RNA transcript, destabilizes it, and reduces new TDP43 protein production. In the neurodegenerative disorder amyotrophic lateral sclerosis (ALS), cytoplasmic mislocalization and accumulation of TDP43 disrupt autoregulation; conversely, inefficient TDP43 autoregulation can lead to cytoplasmic TDP43 deposition and subsequent neurodegeneration. Because TDP43 plays a multifaceted role in maintaining RNA metabolism, its mislocalization and accumulation interrupt several RNA processing pathways that in turn affect RNA stability and gene expression. TDP43-mediated disruption of these pathways-including alternative mRNA splicing, non-coding RNA processing, and RNA granule dynamics-may directly or indirectly contribute to ALS pathogenesis. Therefore, strategies that restore effective TDP43 autoregulation may ultimately prevent neurodegeneration in ALS and related disorders.

KEYWORDS:

Alternative splicing; Autoregulation; Disease; Neurodegeneration; Non-coding RNA; Nonsense mediated mRNA decay; RNA; Stress granule

PMID:
29395044
PMCID:
PMC5997512
[Available on 2019-08-15]
DOI:
10.1016/j.brainres.2018.01.015

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