Macrophage depletion blocks congenital SARM1-dependent neuropathy.

Caitlin B Dingwall, Amy Strickland, Sabrina W Yum, Aldrin Ky Yim, Jian Zhu, Peter L Wang, Yurie Yamada, Robert E Schmidt, Yo Sasaki, A Joseph Bloom, Aaron DiAntonio, Jeffrey Milbrandt

The Journal of clinical investigation 2022 Dec 01

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Axon loss contributes to many common neurodegenerative disorders. In healthy axons, the axon survival factor NMNAT2 inhibits SARM1, the central executioner of programmed axon degeneration. We identified 2 rare NMNAT2 missense variants in 2 brothers afflicted with a progressive neuropathy syndrome. The polymorphisms resulted in amino acid substitutions V98M and R232Q, which reduced NMNAT2 NAD+-synthetase activity. We generated a mouse model to mirror the human syndrome and found that Nmnat2V98M/R232Q compound-heterozygous CRISPR mice survived to adulthood but developed progressive motor dysfunction, peripheral axon loss, and macrophage infiltration. These disease phenotypes were all SARM1-dependent. Remarkably, macrophage depletion therapy blocked and reversed neuropathic phenotypes in Nmnat2V98M/R232Q mice, identifying a SARM1-dependent neuroimmune mechanism as a key driver of disease pathogenesis. These findings demonstrate that SARM1 induced inflammatory neuropathy and highlight the potential of immune therapy as a treatment for this rare syndrome and other neurodegenerative conditions associated with NMNAT2 loss and SARM1 activation.

Citation

Caitlin B Dingwall, Amy Strickland, Sabrina W Yum, Aldrin Ky Yim, Jian Zhu, Peter L Wang, Yurie Yamada, Robert E Schmidt, Yo Sasaki, A Joseph Bloom, Aaron DiAntonio, Jeffrey Milbrandt. Macrophage depletion blocks congenital SARM1-dependent neuropathy. The Journal of clinical investigation. 2022 Dec 01;132(23)