Loss of mouse Stmn2 function causes motor neuropathy

Irune Guerra San Juan, Leslie A. Nash, Kevin S. Smith, Marcel F. Leyton-Jaimes, Menglu Qian, Joseph R. Klim, Francesco Limone, Alexander B. Dorr, Alexander Couto, Greta Pintacuda, Brian J. Joseph, D. Eric Whisenant, Caroline Noble, Veronika Melnik, Deirdre Potter, Amie Holmes, Aaron Burberry, Matthijs Verhage, Kevin Eggan

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Amyotrophic lateral sclerosis (ALS) is characterized by motor neuron degeneration accompanied by aberrant accumulation and loss of function of the RNA-binding protein TDP43. Thus far, it remains unresolved to what extent TDP43 loss of function directly contributes to motor system dysfunction. Here, we employed gene editing to find whether the mouse ortholog of the TDP43-regulated gene STMN2 has an important function in maintaining the motor system. Both mosaic founders and homozygous loss-of-function Stmn2 mice exhibited neuromuscular junction denervation and fragmentation, resulting in muscle atrophy and impaired motor behavior, accompanied by an imbalance in neuronal microtubule dynamics in the spinal cord. The introduction of human STMN2 through BAC transgenesis was sufficient to rescue the motor phenotypes observed in Stmn2 mutant mice. Collectively, our results demonstrate that disrupting the ortholog of a single TDP43-regulated RNA is sufficient to cause substantial motor dysfunction, indicating that disruption of TDP43 function is likely a contributor to ALS.

Original languageEnglish
Pages (from-to)1671-1688.e6
JournalNeuron
Volume110
Issue number10
DOIs
StatePublished - 18 May 2022
Externally publishedYes

Keywords

  • ALS
  • CRISPR
  • microtubules
  • motor neuron
  • motor neuropathy
  • neuromuscular junction
  • SCG10
  • stathmin 2
  • TARDBP
  • TDP43

ASJC Scopus subject areas

  • General Neuroscience

Fingerprint

Dive into the research topics of 'Loss of mouse Stmn2 function causes motor neuropathy'. Together they form a unique fingerprint.

Cite this