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Usage Information

A SARM1-mitochondrial feedback loop drives neuropathogenesis in a Charcot-Marie-Tooth disease type 2A rat model
Yurie Sato-Yamada, … , Aaron DiAntonio, Jeffrey Milbrandt
Yurie Sato-Yamada, … , Aaron DiAntonio, Jeffrey Milbrandt
Published October 26, 2022
Citation Information: J Clin Invest. 2022;132(23):e161566. https://doi.org/10.1172/JCI161566.
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Research Article Neuroscience

A SARM1-mitochondrial feedback loop drives neuropathogenesis in a Charcot-Marie-Tooth disease type 2A rat model

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Abstract

Charcot-Marie-Tooth disease type 2A (CMT2A) is an axonal neuropathy caused by mutations in the mitofusin 2 (MFN2) gene. MFN2 mutations result in profound mitochondrial abnormalities, but the mechanism underlying the axonal pathology is unknown. Sterile α and Toll/IL-1 receptor motif–containing 1 (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, neuromuscular junction (NMJ) abnormalities, muscle atrophy, and mitochondrial abnormalities — all hallmarks of the human disease. We generated Sarm1-KO (Sarm1–/–) and Mfn2H361Y Sarm1 double-mutant rats and found that deletion of Sarm1 rescued axonal, synaptic, muscle, and functional phenotypes, demonstrating that SARM1 was responsible for 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 activated SARM1 and that activated SARM1 fed back on mitochondria to exacerbate the mitochondrial pathology. As such, this work identifies SARM1 inhibition as a therapeutic candidate for the treatment of CMT2A and other neurodegenerative diseases with prominent mitochondrial pathology.

Authors

Yurie Sato-Yamada, Amy Strickland, Yo Sasaki, Joseph Bloom, Aaron DiAntonio, Jeffrey Milbrandt

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Usage data is cumulative from October 2022 through January 2023.

Usage JCI PMC
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Citation downloads 124 0
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