Program: Molecular Genetics and Genomics
Current advisor: Jeffrey Milbrandt, MD, PhD
Undergraduate university: University of Illinois – Urbana-Champaign
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 two rare NMNAT2 missense variants in two brothers afflicted with a progressive neuropathy syndrome. The polymorphisms result in amino acid substitutions, V98M and R232Q, which reduce NMNAT2 NAD+-synthetase activity. We generated a mouse model of the human syndrome and found that Nmnat2V98M/Nmnat2R232Q compound-heterozygous CRISPR mice survive to adulthood but develop progressive motor dysfunction, peripheral axon loss, and macrophage infiltration. These disease phenotypes are all SARM1-dependent. Remarkably, macrophage depletion therapy blocks and reverses neuropathic phenotypes in Nmnat2V98M/R232Q mice, identifying a SARM1-dependent neuroimmune mechanism as a key driver of disease pathogenesis. These findings demonstrate that SARM1 induces an inflammatory neuropathy and highlight the potential of immune therapy to treat this rare syndrome and other neurodegenerative conditions associated with NMNAT2 loss and SARM1 activation.
Wu T, Zhu J, Strickland A, Ko KW, Sasaki Y, Dingwall CB, Yamada Y, Figley MD, Mao X, Neiner A, Bloom AJ, DiAntonio A, Milbrandt J. 2021 Neurotoxins subvert the allosteric activation mechanism of SARM1 to induce neuronal loss. Cell Rep, 37(3):109872.