Project Summary/Abstract:
Axon maintenance is regulated by components of the programmed axon degeneration (AxD) pathway,
most importantly the axon survival factor, NMNAT2, and the chief axon executioner, SARM1, an NAD hydrolase
that initiates local metabolic catastrophe when activated by axon damage. Chronic SARM1 activation that
contributes to degeneration is called sarmopathy, and it is believed to play a role in diseases including
amyotrophic lateral sclerosis (ALS), Charcot-Marie-Tooth disease type 2A, and peripheral neuropathy. SARM1
and NMNAT2 were previously believed to regulate axon integrity exclusively cell-autonomously, but we
discovered that SARM1 plays a role in cell-extrinsic mechanisms of AxD, namely macrophage recruitment and
activation contributing to the initial phase of axon dysfunction and degeneration. We developed a human disease
model featuring pure sarmopathy based on patients with a rare early-onset, progressive polyneuropathy caused
by NMNAT2 mutations. Macrophage depletion delays axon loss and significantly improves motor function even
after the onset of symptom in this model, indicating that SARM1 initiates macrophage-mediated axon elimination
months before stressed axons would otherwise succumb to cell-intrinsic metabolic failure. We also found that
blocking axonal externalization of lyso-phosphatidylserine (lyso-PS), a phagocytic “eat-me” signal that promotes
macrophage clearance of apoptotic cells, delays motor dysfunction in the model. Manipulating lyso-PS was
achieved by virally overexpressing the phosphatidylserine lipase ABHD12 in mouse spinal cord, demonstrating
a completely novel potential therapeutic strategy for peripheral neuropathy.
In this proposal, we outline experiments to elucidate the SARM1-dependent pro-degenerative
neuroinflammatory response. We will characterize immunocytes and other cells in mouse model nerves to
determine their provenance and unique transcriptional profiles to identify key genes and pathways that shape
sarmopathic neuroinflammation. We will test the roles of repair SCs and candidate chemoattractants/ receptors
in SARM1-dependent macrophage recruitment and activation by testing whether sarmopathy is modified in
combination with informative gene knockout models. We will also specifically address the role of
phosphatidylserine (PS) exposure in sarmopathy by manipulating PS and PS receptors genetically in vivo,
including via ABHD12 overexpression. Results of these studies will establish the through-line connecting SARM1
activation, inflammation, and the development of peripheral neurodegenerative diseases, and drive forward the
development of anti-inflammatory axoprotective therapeutics for these devastating disorders.