TDP-43-mediated neurodegeneration: towards a loss-of-function hypothesis?

Trends Mol Med. 2014 Feb;20(2):66-71. doi: 10.1016/j.molmed.2013.11.003. Epub 2013 Dec 16.

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are clinically distinct fatal neurodegenerative disorders. Increasing molecular evidence indicates that both disorders are linked in a continuous spectrum (ALS-FTD spectrum). Neuronal cytoplasmic inclusions consisting of the nuclear TAR DNA-binding protein 43 (TDP-43) are found in the large majority of patients in the ALS-FTD spectrum and dominant mutations in the TDP-43 gene cause ALS. A major unresolved question is whether TDP-43-mediated neuronal loss is caused by toxic gain of function of cytoplasmic aggregates, or by a loss of its normal function in the nucleus. Here we argue that based on recent genetic studies in worms, flies, fish, and rodents, loss of function of TDP-43, rather than toxic aggregates, is the key factor in TDP-43-related proteinopathies.

Keywords: ALS; FTD; TDP-43; loss-of-function; neurodegeneration; proteinopathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism
  • Animals
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism*
  • Frontotemporal Dementia / genetics
  • Frontotemporal Dementia / metabolism
  • Humans
  • Mutation
  • Neurodegenerative Diseases / genetics*
  • Neurodegenerative Diseases / metabolism*
  • Neurons / metabolism
  • Neurons / pathology
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism

Substances

  • DNA-Binding Proteins
  • RNA-Binding Proteins