Portal de Periódicos da CAPES

Loss of mouse Stmn2 function causes motor neuropathy

2022; Cell Press; Volume: 110; Issue: 10 Linguagem: Inglês

10.1016/j.neuron.2022.02.011

1097-4199

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 Benavides Couto, Greta Pintacuda, Brian Joseph, D. Eric Whisenant, Caroline Noble, Veronika Melnik, Deirdre Potter, Amie L. Holmes, Aaron Burberry, Matthijs Verhage, Kevin Eggan,

Neurogenetic and Muscular Disorders Research

Summary 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.