PT  - JOURNAL ARTICLE
AU  - Caitlin B. Dingwall
AU  - Amy Strickland
AU  - Sabrina W. Yum
AU  - Aldrin K. Yim
AU  - Jian Zhu
AU  - Peter L. Wang
AU  - Yurie Yamada
AU  - Robert E. Schmidt
AU  - Yo Sasaki
AU  - A. Joseph Bloom
AU  - Aaron DiAntonio
AU  - Jeffrey Milbrandt
TI  - Macrophage depletion blocks congenital SARM1-dependent neuropathy
AID  - 10.1101/2022.02.26.482110
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.02.26.482110
4099  - http://biorxiv.org/content/early/2022/03/01/2022.02.26.482110.short
4100  - http://biorxiv.org/content/early/2022/03/01/2022.02.26.482110.full
AB  - 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.Competing Interest StatementA.D. and J.M. are co-founders, scientific advisory board members, and shareholders of Disarm Therapeutics, a wholly-owned subsidiary of Eli Lilly. A.J.B. and Y.S. are consultants to Disarm Therapeutics. The authors have no other competing conflicts or financial interests.