The Journal of Clinical Investigation (Dec 2022)

Macrophage depletion blocks congenital SARM1-dependent neuropathy

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

Journal volume & issue
Vol. 132, no. 23

Abstract

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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.

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