SARM1 promotes axonal, synaptic, and mitochondrial pathologies in Charcot-Marie-Tooth disease type 2A

Charcot-Marie-Tooth disease (CMT) type 2A is an axonal neuropathy caused by mutations in the mitofusin 2 (MFN2) gene. MFN2 mutations result in profound mitochondrial abnormalities, but the mechanism underlying axonal pathology is unknown. SARM1, the central executioner of axon degeneration, can induce neuropathy and is activated by dysfunctional mitochondria. We tested the role of SARM1 in a rat model carrying a dominant CMT2A mutation (Mfn2H361Y) that exhibits progressive dying-back axonal degeneration, NMJ abnormalities, muscle atrophy, and mitochondrial abnormalities, all hallmarks of the human disease. We generated Sarm1 knockout and Mfn2H361Y, Sarm1 double mutant rats and find that deletion of SARM1 rescues axonal, synaptic, and muscle phenotypes, demonstrating that SARM1 induces much of the neuropathology in this model. Despite the presence of mutant Mfn2 protein in these double mutant rats, loss of SARM1 also dramatically suppressed many mitochondrial defects, including the number, size, and cristae density defects of synaptic mitochondria. This surprising finding indicates that dysfunctional mitochondria activate SARM1, and activated SARM1 feeds back on mitochondria to exacerbate mitochondrial pathology. As such, this work identifies SARM1 inhibition as an exciting therapeutic candidate for the treatment of CMT2A and other neurodegenerative diseases with prominent mitochondrial pathology. ### Competing Interest Statement A.J.B. and Y.S. have consulted for Disarm Therapeutics. A.D. and J.M. were cofounders, scientific advisory board members, and shareholders of Disarm Therapeutics, a wholly owned subsidiary of Eli Lilly & Company.