Burst mitofusin activation reverses neuromuscular dysfunction in murine CMT2A

• DOI: 10.7554/elife.61119
• Publication Date: 2020-10-19T12:33:51Z
• Authors: Antonietta Franco; Xiawei Dang; Emily K Walton; Joshua N Ho; Barbara Zablocka; Cindy Ly; Timothy M Miller; Robert H Baloh; Michael E Shy; Andrew S Yoo; Gerald W Dorn
• Keywords: Male; 0301 basic medicine; QH301-705.5; Science; Neuromuscular Junction; mitofusin; GTP Phosphohydrolases; Mitochondrial Proteins; Mice; 03 medical and health sciences; CMT2A; Charcot-Marie-Tooth Disease; Animals; Biology (General); Motor Neurons; Muscle Cells; Q; R; Cell Biology; Axons; Mitochondria, Muscle; 3. Good health; mitochondria; Mice, Inbred C57BL; Mutation; Medicine; Female

Charcot-Marie-Tooth disease type 2A (CMT2A) is an untreatable childhood peripheral neuropathy caused by mutations of the mitochondrial fusion protein, mitofusin (MFN) 2. Here, pharmacological activation endogenous normal mitofusins overcame dominant inhibitory effects CMT2A mutants in reprogrammed human patient motor neurons, reversing hallmark stasis and fragmentation independent causal MFN2 mutation. In mice expressing T105M, intermittent with a small molecule, MiM111, normalized neuromuscular dysfunction, reversed pre-treatment axon skeletal myocyte atrophy, enhanced regrowth increasing transport within axons promoting vivo localization to junctional synapses. MiM111-treated T105M mouse neurons exhibited accelerated primary outgrowth greater post-axotomy regrowth, linked motility. MiM111 first pre-clinical candidate for CMT2A.Charcot-Marie-Tooth rare genetic where dying back nerve cells leads muscle loss arms legs, causing permanent disability. There no known treatment. this form CMT, protein called 2 damage structures inside as mitochondria. Mitochondria generate most chemical energy power cell, but when mutated, mitochondria are less healthy unable move depriving energy. This particularly causes problems long that stretch from spinal cord arm leg muscles. Now, Franco, Dang et al. wanted see whether re-activating could correct restore connections The researchers tested new class drug activator on grown laboratory after being taken people suffering CMT2A, also model disease. Mitofusin activators improved structure, fitness movement both cells. then mutation found it stimulate nerves regrow so reverse weakness. time scientists have succeeded humans. However, these drugs will still need go through extensive testing clinical trials before made widely available patients. If approved, may be beneficial patients other conditions