Macrophage depletion blocks congenital SARM1-dependent neuropathy
Caitlin B. Dingwall, … , Aaron DiAntonio, Jeffrey Milbrandt
Caitlin B. Dingwall, … , Aaron DiAntonio, Jeffrey Milbrandt
Published October 26, 2022
Citation Information: J Clin Invest. 2022;132(23):e159800. https://doi.org/10.1172/JCI159800.
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Research Article Neuroscience

Macrophage depletion blocks congenital SARM1-dependent neuropathy

Abstract

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.

Authors

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

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Figure 5

Neuronal SARM1 is required for Nmnat2V98M/R232Q neuropathy.

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Neuronal SARM1 is required for Nmnat2V98M/R232Q neuropathy. (A) Relative...
(A) Relative cADPR levels in sciatic nerves of 2-month-old WT (n = 3), Nmnat2V98M/R232Q (n = 4), and Nmnat2V98M/R232Q; Sarm1-KO (n = 3) mice. Values normalized to WT cADPR levels (set to 1). Statistical significance determined by a Student’s unpaired t test. (B) Average tibialis anterior weight by body weight for WT, Nmnat2V98M/R232Q, and Nmnat2V98M/R232Q; Sarm1-KO mice in 2- and 9–12-month-old mice (n = 3–11 mice per age cohort, per genotype). (C) Average time suspended from an inverted screen (max. 120 seconds) for WT (n = 3–7), Nmnat2V98M/R232Q (n = 3–21), and Nmnat2V98M/R232Q; Sarm1-KO (n = 7–13) mice. (D–F) Representative images of sciatic (D), femoral (E), and sural (F) nerves in 9–12-month-old Nmnat2V98M/R232Q; Sarm1-KO mice. Scale bars: 50 μm. Percent axonal area/total nerve area is calculated below each corresponding nerve (n = 3–11 mice per age cohort, per genotype). Statistical significance was determined by 2-way ANOVA with multiple comparisons. (G) Schematic of AAV-SARM1-DN gene therapy experiment. (H) Percent initial performance on inverted screen test at 2 months and 6 months for EGFP (control) (n = 6) or SARM1-DN–injected (n = 7) Nmnat2V98M/R232Q mice. (I) Quantification of GFP fluorescence in the spinal cord of SARM1-DN injected Nmnat2V98M/R232Q mice, stratified by rescue (Rescue was determined as an endpoint performance (6m) greater than the mean control arm endpoint performance.) All data are presented as mean ± SEM. Statistical significance within treatment group was determined by a Student’s paired, 2-tailed t test. Statistical significance between treatment groups determined by a Student’s unpaired, 2-tailed t test.*P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.