This study reports the successful creation of the Charcot-Marie-Tooth type 2A disease (CMT2A) rodent (rat) model and the rescue of its pathology by Sarm1 loss-of-function in various histological aspects. CMT2A is a common hereditary peripheral neuropathy caused by mutations in Mitofusin 2(MFN2), which plays a critical role in mitochondrial functions. There is no disease-modifying treatment now. Sarm1 activation is critical for programmed axon death. Sarm1 is a NAD(P)ase cleaving NAD+, leading to a metabolic collapse with loss of ATP. The authors initially generated the knock-in rat carrying the dominant human CMT2A mutation (Mfn2^H361Y/+) in one allele. The rat line recapitulated CMT2A neuromuscular phenotypes, including progressive neurodegeneration and muscle wasting with decreased NAD+ levels in peripheral nerves. The success of this rodent model per se is one of the fundamental discoveries in the field because the mice with a similar mutation did not display axonal degeneration, the hallmark pathology of human CMT2A. In addition, the authors hypothesized genetic interactions between Mfn2 and Sarm1.
Interestingly, Sarm1 knockout nearly ultimately rescued the histopathological characteristics in Mfn2^H361Y/+ mutants, i.e., protection from axonal degeneration, muscle atrophy, and neuromuscular junctions (NMJs) degeneration. Surprisingly, Sarm1 knockout also restored mitochondrial morphological abnormalities/motility deficits in Mfn2 mutation. Although the reviewer does not find behavioral data or mechanistic insights on how Sarm1 was rescued from axonal degeneration and mitochondrial defects, their discoveries would substantially impact designing new therapeutic strategies for CMT2A patients.
