Axonal transport of TDP-43 mRNA granules is impaired by ALS-causing mutations

Neuron. 2014 Feb 5;81(3):536-543. doi: 10.1016/j.neuron.2013.12.018.

Abstract

The RNA-binding protein TDP-43 regulates RNA metabolism at multiple levels, including transcription, RNA splicing, and mRNA stability. TDP-43 is a major component of the cytoplasmic inclusions characteristic of amyotrophic lateral sclerosis and some types of frontotemporal lobar degeneration. The importance of TDP-43 in disease is underscored by the fact that dominant missense mutations are sufficient to cause disease, although the role of TDP-43 in pathogenesis is unknown. Here we show that TDP-43 forms cytoplasmic mRNP granules that undergo bidirectional, microtubule-dependent transport in neurons in vitro and in vivo and facilitate delivery of target mRNA to distal neuronal compartments. TDP-43 mutations impair this mRNA transport function in vivo and in vitro, including in stem cell-derived motor neurons from ALS patients bearing any one of three different TDP-43 ALS-causing mutations. Thus, TDP-43 mutations that cause ALS lead to partial loss of a novel cytoplasmic function of TDP-43.

Publication types

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

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / pathology*
  • Animals
  • Animals, Genetically Modified
  • Axonal Transport / genetics*
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • DNA-Binding Proteins / genetics*
  • Drosophila
  • Drosophila Proteins / genetics
  • Humans
  • Kruppel-Like Factor 4
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism
  • Luminescent Proteins / genetics
  • Mice
  • Mitochondria / metabolism
  • Motor Neurons / metabolism*
  • Motor Neurons / ultrastructure
  • Mutation / genetics*
  • Octamer Transcription Factor-3 / genetics
  • Octamer Transcription Factor-3 / metabolism
  • RNA, Messenger / metabolism*
  • RNA-Binding Proteins / metabolism
  • SOXB1 Transcription Factors / genetics
  • SOXB1 Transcription Factors / metabolism

Substances

  • DNA-Binding Proteins
  • Drosophila Proteins
  • Kruppel-Like Factor 4
  • Kruppel-Like Transcription Factors
  • Luminescent Proteins
  • Octamer Transcription Factor-3
  • POU5F1 protein, human
  • RNA, Messenger
  • RNA-Binding Proteins
  • SOX2 protein, human
  • SOXB1 Transcription Factors
  • Stau1 protein, mouse