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
Program in Chemical Biology
Biochemistry and Molecular Pharmacology
Document TypeJournal Article
Amino Acids, Peptides, and Proteins
Enzymes and Coenzymes
Nervous System Diseases
Neuroscience and Neurobiology
MetadataShow full item record
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
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/37989
RightsCopyright © 2021, Loring et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Except where otherwise noted, this item's license is described as Copyright © 2021, Loring et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.