ArticleThe Journal of clinical investigation2022
A SARM1-mitochondrial feedback loop drives neuropathogenesis in a Charcot-Marie-Tooth disease type 2A rat model.
Article in The Journal of clinical investigation, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 50 citations in OpenAlex.
- Direct activation of SARM1 by dsDNA is not supported by biochemical and cellular evidence.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Review
- Neuromuscular Dysfunction and Charcot-Marie-Tooth Disease Reversal in Mfn2 T105M Knock-In Rats.International journal of molecular sciences · 2026Article
- Complex Contributions of Methylglyoxal to Pain, Axon Degeneration, and Diabetic Peripheral Neuropathy.Journal of neurochemistry · 2026Review
- Junctions in Jeopardy: the neuromuscular junction is a selective pathological target in Charcot-Marie-Tooth disease.Mammalian genome : official journal of the International Mammalian Genome Society · 2026Review
- Advancing Peripheral Nerve Regeneration (Nerve SPACE 2025).Journal of hand surgery global online · 2026Article
- Cristae: bridging bioenergetic hubs and compartmental barriers in mitochondrial homeostasis.Cell death & disease · 2026Review
- Axonopathy: mechanisms and potential therapeutic targets for neurodegenerative diseases.Translational neurodegeneration · 2026Review
- Histone methyltransferase SET-18/SMYD2-mediated activation of NADase TIR-1d/SARM1 increases mtROS to promote aging.iScience · 2026Article
- Charcot-Marie-Tooth disease and related neuropathies.Nature reviews. Disease primers · 2026Review
- Hyperglycemia promotes SIRT3-mediated deacetylation of SARM1 to exacerbate diabetic peripheral neuropathy in mice.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Hereditary Polyneuropathies in the Era of Precision Medicine: Genetic Complexity and Emerging Strategies.Genes · 2026Review
- Appraisal of CRISPR Technology as an Innovative Screening to Therapeutic Toolkit for Genetic Disorders.Molecular biotechnology · 2026Review
- Biophysical simulation enables segmentation and nervous system atlas mapping for image first spatial omics.NPJ systems biology and applications · 2025Article
- Advances and challenges in modeling Charcot-Marie-Tooth type 2A using iPSC-derived models.Stem cell reports · 2025Review
- SARM1 Inhibition in Three Mouse Models of Charcot-Marie-Tooth Disease.Journal of the peripheral nervous system : JPNS · 2025Article
- Genetic Deletion of Sarm1 in Mouse Models of Three Neurological Diseases.Journal of the peripheral nervous system : JPNS · 2025Article
- SARM1: The Checkpoint of Axonal Degeneration in the Nervous System Disorders.Molecular neurobiology · 2025Review
- Suppressing phagocyte activation by overexpressing the phosphatidylserine lipase ABHD12 preserves sarmopathic nerves.iScience · 2025Article
- Diverse cell types establish a pathogenic immune environment in peripheral neuropathy.Journal of neuroinflammation · 2025Article
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
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.
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