TDP43 and RNA instability in amyotrophic lateral sclerosis

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Alternative Splicing
  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / metabolism
  • Animals
  • Cytoplasm / metabolism
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Fragile X Mental Retardation Protein / genetics
  • Humans
  • Motor Neurons / metabolism
  • RNA / genetics
  • RNA / metabolism
  • RNA Stability*


  • DNA-Binding Proteins
  • FMR1 protein, human
  • TARDBP protein, human
  • TDP-43 protein, mouse
  • Tardbp protein, rat
  • Fragile X Mental Retardation Protein
  • RNA