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.
View: Text | PDF
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

×

Figure 3

Nmnat2 variants cause progressive axon loss in mice.

Options: View larger image (or click on image) Download as PowerPoint
Nmnat2 variants cause progressive axon loss in mice. (A–C) Representati...
(A–C) Representative images of sciatic (A), femoral (B), and sural (C) nerves in 9–12-month-old Nmnat2V98M/R232Q (n = 9) or WT (n = 5) mice. Percent axonal area/total nerve area are indicated to the right (n = 4–11 mice per age cohort, per genotype). Scale bars: 50 μm. (D) Nmnat2V98M/R232Q sciatic nerve (2 months): dense population of large and small myelinated axons with little intervening extracellular space. (E) Nmnat2V98M/R232Q sciatic nerve (2 months): macrophage containing axonal and myelin debris in the endoneurial. (F) Nmnat2V98M/R232Q sciatic nerve (12 months): patches of marked axon loss with increased collagen and wispy processes of SC. Scattered macrophages with axonal and myelin debris were identified. (G) Nmnat2V98M/R232Q sciatic nerve (12 months): presence of large perineurial droplets of neutral fat. (H) Representative images of ChAT immunostaining in 12-month-old Nmnat2V98M/R232Q (n = 4) or WT (n = 3) spinal cord (ventral horn), scale bars: 50 μm. Quantification of number of ChAT+ motor neuron cell bodies in the ventral horn to the right. All data are presented as mean ± SEM. Statistical significance determined by Student’s unpaired, 2-tailed t test or 2-way ANOVA with multiple comparisons. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.