Loss of Stathmin-2, a hallmark of TDP-43-associated ALS, causes motor neuropathy

Cell Rep. 2022 Jun 28;39(13):111001. doi: 10.1016/j.celrep.2022.111001.


TDP-43 mediates proper Stathmin-2 (STMN2) mRNA splicing, and STMN2 protein is reduced in the spinal cord of most patients with amyotrophic lateral sclerosis (ALS). To test the hypothesis that STMN2 loss contributes to ALS pathogenesis, we generated constitutive and conditional STMN2 knockout mice. Constitutive STMN2 loss results in early-onset sensory and motor neuropathy featuring impaired motor behavior and dramatic distal neuromuscular junction (NMJ) denervation of fast-fatigable motor units, which are selectively vulnerable in ALS, without axon or motoneuron degeneration. Selective excision of STMN2 in motoneurons leads to similar NMJ pathology. STMN2 knockout heterozygous mice, which better model the partial loss of STMN2 protein found in patients with ALS, display a slowly progressive, motor-selective neuropathy with functional deficits and NMJ denervation. Thus, our findings strongly support the hypothesis that STMN2 reduction owing to TDP-43 pathology contributes to ALS pathogenesis.

Keywords: CP: Neuroscience; NMNAT2; SARM1; SCG-10; axon degeneration; motor neuron; neurodegeneration; neuropathy; stathmin.

Publication types

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

MeSH terms

  • Amyotrophic Lateral Sclerosis* / genetics
  • Amyotrophic Lateral Sclerosis* / metabolism
  • Amyotrophic Lateral Sclerosis* / pathology
  • Animals
  • DNA-Binding Proteins* / genetics
  • DNA-Binding Proteins* / metabolism
  • Mice
  • Mice, Knockout
  • Motor Neurons / metabolism
  • Motor Neurons / pathology
  • Stathmin* / deficiency
  • Stathmin* / genetics
  • Stathmin* / metabolism


  • DNA-Binding Proteins
  • Stathmin
  • Stmn2 protein, mouse
  • TDP-43 protein, mouse