SIRT2‐knockdown rescues GARS‐induced Charcot‐Marie‐Tooth neuropathy

Abstract

Charcot‐Marie‐Tooth disease is the most common inherited peripheral neuropathy. Dominant mutations in the glycyl‐tRNA synthetase (GARS) gene cause peripheral nerve degeneration and lead to CMT disease type 2D. The underlying mechanisms of mutations in GARS (GARSCMT2D) in disease pathogenesis are not fully understood. In this study, we report that wild‐type GARS binds the NAD+‐dependent deacetylase SIRT2 and inhibits its deacetylation activity, resulting in the acetylated α‐tubulin, the major substrate of SIRT2. The catalytic domain of GARS tightly interacts with SIRT2, which is the most CMT2D mutation localization. However, CMT2D mutations in GARS cannot inhibit SIRT2 deacetylation, which leads to a decrease of acetylated α‐tubulin. 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 α‐tubulin deacetylation in mutant GARS‐induced neuropathies and provide new perspectives for targeting SIRT2 as a potential therapy against hereditary axonopathies.

NAD+ Metabolism and Diseases with Motor Dysfunction

“…However, these results may not relate to NAD + availability but instead relate more to the specific mutation that caused CMT. In this specific CMT type, the mutated protein, GARS, binds directly to Sirt2 to affect normal Sirt2 function [117]. The benefits of Sirt2 knockdown in this case would have no relation to NAD + availability.…”

Drosophila Models for Charcot–Marie–Tooth Neuropathy Related to Aminoacyl-tRNA Synthetases

“…The neomorphic conformation of hGARS1 induced by CMT mutations [88] disrupted the Sirt2/hGARS1 interaction. As a consequence, hGARS1 CMT was not able to inhibit Sirt2 activity, thus leading to hyperacetylated α -tubulin levels [67]. Importantly, these results were validated in vivo utilizing the hGARS1 CMT D. melanogaster model.…”

“…The main-tenance of the correct α-tubulin acetylation status is therefore especially important to the functioning of the long axons of peripheral nerves. Binding of hGARS1 WT to Sirt2 inhibited its enzymatic function in NSC-34 motor-neuron-like mouse cells [67]. The neomorphic conformation of hGARS1 induced by CMT mutations [88] disrupted the Sirt2/hGARS1 interaction.…”

“…Nervous system (nSyb-GAL4) [43] hGARS1 E71G, G240R, G526R Glutamatergic neurons (OK371-GAL4) [44,67,68] GFS morphological and electrophysiological deficits…”

“…Recently, Zhao et al reported that the altered conformation of GARS1 CMT [88] is capable of disturbing important protein-protein associations, such as the interaction of hGARS1 WT with the histone deacetylase Sirt2 [67]. Sirt2 is a major regulator of α-tubulin acetylation [91] which regulates microtubule stability and vesicular transport.…”