Src inhibition attenuates polyglutamine-mediated neuromuscular degeneration in spinal and bulbar muscular atrophy

Nat Commun. 2019 Sep 19;10(1):4262. doi: 10.1038/s41467-019-12282-7.


Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by an expanded CAG repeat in the androgen receptor (AR) gene. Here, we perform a comprehensive analysis of signaling pathways in a mouse model of SBMA (AR-97Q mice) utilizing a phosphoprotein assay. We measure the levels of 17 phosphorylated proteins in spinal cord and skeletal muscle of AR-97Q mice at three stages. The level of phosphorylated Src (p-Src) is markedly increased in the spinal cords and skeletal muscles of AR-97Q mice prior to the onset. Intraperitoneal administration of a Src kinase inhibitor improves the behavioral and histopathological phenotypes of the transgenic mice. We identify p130Cas as an effector molecule of Src and show that the phosphorylated p130Cas is elevated in murine and cellular models of SBMA. These results suggest that Src kinase inhibition is a potential therapy for SBMA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bulbo-Spinal Atrophy, X-Linked / genetics
  • Bulbo-Spinal Atrophy, X-Linked / pathology*
  • Bulbo-Spinal Atrophy, X-Linked / therapy
  • Cell Line
  • Crk-Associated Substrate Protein / metabolism
  • Disease Models, Animal
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Muscle, Skeletal / metabolism*
  • Phosphorylation
  • Proto-Oncogene Proteins pp60(c-src) / genetics
  • Proto-Oncogene Proteins pp60(c-src) / metabolism*
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Receptors, Androgen / genetics*
  • Spinal Cord / metabolism*
  • src-Family Kinases / antagonists & inhibitors*


  • AR protein, mouse
  • Crk-Associated Substrate Protein
  • RNA, Small Interfering
  • Receptors, Androgen
  • Proto-Oncogene Proteins pp60(c-src)
  • src-Family Kinases