UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology; Program in Chemical Biology; Department of Neurobiology; Byrne Lab; Thompson Lab; Graduate School of Biomedical Sciences

Publication Date

2021-06-29

Document Type

Article

Disciplines

Amino Acids, Peptides, and Proteins | Biochemistry | Enzymes and Coenzymes | Nervous System Diseases | Neuroscience and Neurobiology

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.

Keywords

C. elegans, SARM1, biochemistry, chemical biology, enzymology, kinetics, neuroscience, phase transition, wallerian degeneration

Rights and Permissions

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.

DOI of Published Version

10.7554/eLife.66694

Source

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

Journal/Book/Conference Title

eLife

Related Resources

Link to Article in PubMed

PubMed ID

34184985

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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