Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 132, Issue 23, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI159800
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Funding
- National Institutes of Health [R01NS119812, R01NS087632, R37NS065053, RF1AG013730]
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This study identified rare NMNAT2 gene variants associated with a neuropathy syndrome and demonstrated the importance of SARM1-related neuroimmune mechanisms in disease pathogenesis. Macrophage depletion therapy was shown to block and reverse neuropathic phenotypes in mice with NMNAT2 mutations.
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.
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