SIRT2-knockdown Rescues GARS-induced Charcot-Marie-Tooth Neuropathy

Charcot-Marie-Tooth disease is the most common inherited peripheral neuropathy. Dominant mutations in glycyl-tRNA synthetase (GARS) gene cause peripheral nerve degeneration and lead to CMT disease type 2D. Mutations in GARS (GARSCMT2D) show partial loss-of-function features, suggesting that tRNA-charging deficits play a role in disease pathogenesis, but the underlying mechanisms are not fully understood. In this study we report that wild-type GARS tightly binds the NAD+-dependent deacetylase SIRT2 and inhibits its deacetylation activity, resulting in the hyperacetylated -tubulin, the major substrate of SIRT2. Previous studies showed that acetylation of -tubulin protects microtubules from mechanical breakage and keep axonal transportation. However, CMT2D mutations in GARS can not inhibit SIRT2 deacetylation, which leads to decrease acetylated -tubulin and severe axonal transport deficits. Genetic reduction of SIRT2 in the Drosophila model rescues the GARS-induced axonal CMT neuropathy and extends the life span. Our findings demonstrate the pathogenic role of SIRT2-dependent -tubulin deacetylation in mutant GARS-induced neuropathies and provide new perspectives for targeting SIRT2 as a potential therapy against hereditary axonopathies.