Abstract
Sterile alpha and toll/interleukin receptor (TIR) motif-containing protein 1 (SARM1) is a neuronally expressed NAD+ glycohydrolase whose activity is increased in response to stress. NAD+ depletion triggers axonal degeneration, which is a characteristic feature of neurological diseases. Notably, loss of SARM1 is protective in murine models of peripheral neuropathy and traumatic brain injury. Herein, we report that citrate induces a phase transition that enhances SARM1 activity by ~2000-fold. This phase transition can be disrupted by mutating a residue involved in multimerization, G601P. This mutation also disrupts puncta formation in cells. We further show that citrate induces axonal degeneration in C. elegans that is dependent on the C. elegans orthologue of SARM1 (TIR-1). Notably, citrate induces the formation of larger puncta indicating that TIR-1/SARM1 multimerization is essential for degeneration in vivo. These findings provide critical insights into SARM1 biology with important implications for the discovery of novel SARM1-targeted therapeutics.
Highlights
Despite diverse clinical manifestations, axonal degeneration is an underlying feature of traumatic brain injury, peripheral neuropathies, and other neurodegenerative diseases, including Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease
We further show that citrate induces axonal degeneration in C. elegans that is dependent on the C. elegans orthologue of SARM1 (i.e. toll/interleukin receptor (TIR)–1)
We found that the addition of PEG or citrate led to a time-dependent decrease in NAD+ levels that coincided with increased levels of nicotinamide and a mixture of ADPR and cADPR (Figure 5A–B, Figure 5—figure supplement 1A–B)
Summary
Axonal degeneration is an underlying feature of traumatic brain injury, peripheral neuropathies, and other neurodegenerative diseases, including Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease. Enzymatic activity is 800-fold higher in lysates or when activity is measured on–bead (Essuman et al, 2017; Horsefield et al, 2019; Loring et al, 2020a) These data indicate that the pure protein does not fully recapitulate all features of SARM1 catalysis. Citrate induces the formation of larger puncta indicating that TIR–1/SARM1 undergoes a phase transition that is essential for degeneration in vivo These findings will aid efforts to therapeutically target SARM1 to treat neurodegenerative diseases as they improve our understanding of SARM1 activation and its role as a critical switch in the degenerative process resulting in catastrophic axonal fragmentation
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