Genetic ablation of Sarm1 attenuates axonal degeneration in a mouse model of CMT2J
- 1Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milan, Italy
Abstract
Charcot-Marie-Tooth (CMT) disease is the most common inherited neuropathy, affecting approximately 1 in 2,500 individuals, and comprises a clinically and genetically heterogeneous group of disorders involving more than 100 genes. Mutations in myelin protein zero (MPZ) typically cause the demyelinating form CMT1B, whereas the T124M substitution gives rise to CMT2J, a late-onset, predominantly axonal neuropathy with minimal myelin involvement. We previously generated a MpzT124M mouse model that recapitulates key features of the human disease, including progressive axonal degeneration and fibre loss in peripheral nerves. Because SARM1 (sterile and TIR motif-containing protein 1) is a central executioner of programmed axonal degeneration, we crossed MpzT124M mice with Sarm1-null animals and assessed electrophysiological, morphological, and molecular parameters in both heterozygous and homozygous mutants. Sarm1 deletion did not rescue electrophysiological deficits in either genotype. However, in 12-month-old homozygous MpzT124M/T124M mice, Sarm1 ablation partially reduced axonal degeneration in peripheral nerves and lowered plasma neurofilament light chain, a biomarker of neurodegeneration. In heterozygous MpzT124M/+ mice, where axonal degeneration develops more slowly, Sarm1 deletion was associated with improved motor performance and reduced morphological signs of disease by 18 months of age. Together, these findings indicate that SARM1 contributes to axonal degeneration in CMT2J and that its ablation confers partial protection, although it is insufficient to fully prevent disease progression, supporting SARM1 as a therapeutically relevant target in MPZ-associated axonal neuropathy despite incomplete disease rescue.
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BibTeX
@misc{claessens2026genetic,
title = {{Genetic ablation of Sarm1 attenuates axonal degeneration in a mouse model of CMT2J}},
author = {A. Claessens and R. De Blasis and C. Ferri and S. Valenzano and U. Del Carro and A. Mandelli and R. Furlan and Y. Sasaki and M. L. Feltri and L. Wrabetz and G. Shackleford and M. D'Antonio},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.28.762421},
url = {https://www.biorxiv.org/content/10.64898/2026.10.28.762421v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Genetic ablation of Sarm1 attenuates axonal degeneration in a mouse model of CMT2J
AU - A. Claessens
AU - R. De Blasis
AU - C. Ferri
AU - S. Valenzano
AU - U. Del Carro
AU - A. Mandelli
AU - R. Furlan
AU - Y. Sasaki
AU - M. L. Feltri
AU - L. Wrabetz
AU - G. Shackleford
AU - M. D'Antonio
PY - 2026
DA - 2026/10/28
PB - bioRxiv
DO - 10.64898/2026.10.28.762421
UR - https://www.biorxiv.org/content/10.64898/2026.10.28.762421v1
AB - Charcot-Marie-Tooth (CMT) disease is the most common inherited neuropathy, affecting approximately 1 in 2,500 individuals, and comprises a clinically and genetically heterogeneous group of disorders involving more than 100 genes. Mutations in myelin protein zero (MPZ) typically cause the demyelinating form CMT1B, whereas the T124M substitution gives rise to CMT2J, a late-onset, predominantly axonal neuropathy with minimal myelin involvement. We previously generated a MpzT124M mouse model that recapitulates key features of the human disease, including progressive axonal degeneration and fibre loss in peripheral nerves. Because SARM1 (sterile and TIR motif-containing protein 1) is a central executioner of programmed axonal degeneration, we crossed MpzT124M mice with Sarm1-null animals and assessed electrophysiological, morphological, and molecular parameters in both heterozygous and homozygous mutants. Sarm1 deletion did not rescue electrophysiological deficits in either genotype. However, in 12-month-old homozygous MpzT124M/T124M mice, Sarm1 ablation partially reduced axonal degeneration in peripheral nerves and lowered plasma neurofilament light chain, a biomarker of neurodegeneration. In heterozygous MpzT124M/+ mice, where axonal degeneration develops more slowly, Sarm1 deletion was associated with improved motor performance and reduced morphological signs of disease by 18 months of age. Together, these findings indicate that SARM1 contributes to axonal degeneration in CMT2J and that its ablation confers partial protection, although it is insufficient to fully prevent disease progression, supporting SARM1 as a therapeutically relevant target in MPZ-associated axonal neuropathy despite incomplete disease rescue.
ER -