Abstract Details

Src Inhibition Attenuates Polyglutamine-mediated Neuromuscular Degeneration in Spinal and Bulbar Muscular Atrophy
General Neurology
S51 - General Neurology: Models of Clinical Care and Disease (2:48 PM-3:00 PM)
010
SBMA is a neuromuscular disease caused by the expanded CAG repeats in the androgen receptor (AR) gene. The pathological mechanism by which the polyglutamine-expanded AR mutant induces neuromuscular degeneration remains to be elucidated. 
We aimed to develop the therapeutics targeting the cardinal pathogenesis of spinal and bulbar muscular atrophy (SBMA). 
We investigated the expression levels of 17 phosphorylated proteins using Bio-rad Bio-plex assays, in the spinal cord and skeletal muscle specimen of the mouse model of SBMA (AR-97Q mice) at three stages: pre-onset, early symptomatic, and advanced. Based on the findings in the assays, we analyzed the activation levels of Src pathway and evaluated the efficacy of Src kinase inhibitor (SKI) on cellular and mouse models of SBMA. We also investigated the alteration of phosphorylation levels of Src effector molecules using SKI-treated cellular and mouse models of SBMA. We further investigated the mechanisms of Src activation in SBMA focusing on the interaction of Src with AR.
In Bio-plex assays, the expression level of phosphorylated Src (p-Src) was markedly up-regulated in the spinal cords and skeletal muscles of AR-97Q mice before the onset of neurological symptoms. In spinal cord, the activation of Src sustained until the advanced stage of the disease. Src pathway was also up-regulated in neuronal and muscular cellular models of SBMA. The intraperitoneal administration of A419259 trihydrochloride, an SKI, improved the phenotypes and lifespan of AR-97Q mice (N=24) compared with the control (N=22). We identified p130Cas as effector molecules of Src, and also detected that the interaction of AR and Src was crucial to activate Src pathway in the pathogenesis of SBMA.
Up-regulation of Src pathway has a strong impact on the pathophysiology of SBMA and SKI is a potential therapy for SBMA.
Authors/Disclosures

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