A phase transition enhances the catalytic activity of SARM1, an NAD(+) glycohydrolase involved in neurodegeneration
AuthorsLoring, Heather S.
Czech, Victoria L.
Icso, Janneke D.
O'Connor, Lauren C.
Byrne, Alexandra B.
Thompson, Paul R.
UMass Chan AffiliationsGraduate School of Biomedical Sciences
Department of Neurobiology
Program in Chemical Biology
Department of Biochemistry and Molecular Pharmacology
Amino Acids, Peptides, and Proteins
Enzymes and Coenzymes
Nervous System Diseases
Neuroscience and Neurobiology
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AbstractSterile 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.
Loring HS, Czech VL, Icso JD, O'Connor L, Parelkar SS, Byrne AB, Thompson PR. A phase transition enhances the catalytic activity of SARM1, an NAD+ glycohydrolase involved in neurodegeneration. Elife. 2021 Jun 29;10:e66694. doi: 10.7554/eLife.66694. PMID: 34184985; PMCID: PMC8266388. Link to article on publisher's site