ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair

Nat Neurosci. 2019 Feb;22(2):167-179. doi: 10.1038/s41593-018-0300-4. Epub 2019 Jan 14.

Abstract

The findings that amyotrophic lateral sclerosis (ALS) patients almost universally display pathological mislocalization of the RNA-binding protein TDP-43 and that mutations in its gene cause familial ALS have nominated altered RNA metabolism as a disease mechanism. However, the RNAs regulated by TDP-43 in motor neurons and their connection to neuropathy remain to be identified. Here we report transcripts whose abundances in human motor neurons are sensitive to TDP-43 depletion. Notably, expression of STMN2, which encodes a microtubule regulator, declined after TDP-43 knockdown and TDP-43 mislocalization as well as in patient-specific motor neurons and postmortem patient spinal cord. STMN2 loss upon reduced TDP-43 function was due to altered splicing, which is functionally important, as we show STMN2 is necessary for normal axonal outgrowth and regeneration. Notably, post-translational stabilization of STMN2 rescued neurite outgrowth and axon regeneration deficits induced by TDP-43 depletion. We propose that restoring STMN2 expression warrants examination as a therapeutic strategy for ALS.

Publication types

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

MeSH terms

  • Amyotrophic Lateral Sclerosis / metabolism*
  • Axons / metabolism
  • Cell Line
  • DNA-Binding Proteins / metabolism*
  • Down-Regulation
  • Female
  • Humans
  • Induced Pluripotent Stem Cells
  • Male
  • Membrane Proteins / metabolism*
  • Motor Neurons / metabolism*
  • Spinal Cord / metabolism

Substances

  • DNA-Binding Proteins
  • Membrane Proteins
  • STMN2 protein, human
  • TDP-43 protein, human