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A phase transition enhances the catalytic activity of SARM1, an NAD+ glycohydrolase involved in neurodegeneration
- Source :
- eLife, Vol 10 (2021), eLife
- Publication Year :
- 2021
- Publisher :
- eLife Sciences Publications Ltd, 2021.
-
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.
- Subjects :
- 0301 basic medicine
Wallerian degeneration
SARM1
QH301-705.5
enzymology
Science
Chemical biology
Degeneration (medical)
medicine.disease_cause
Citric Acid
General Biochemistry, Genetics and Molecular Biology
Receptors, G-Protein-Coupled
03 medical and health sciences
NAD+ Nucleosidase
0302 clinical medicine
Biochemistry and Chemical Biology
In vivo
medicine
Animals
Biology (General)
Caenorhabditis elegans
Caenorhabditis elegans Proteins
Mutation
General Immunology and Microbiology
Chemistry
General Neuroscience
Neurodegeneration
wallerian degeneration
General Medicine
medicine.disease
Cell biology
030104 developmental biology
phase transition
kinetics
C. elegans
Interleukin receptor
Medicine
NAD+ kinase
030217 neurology & neurosurgery
Research Article
Neuroscience
Subjects
Details
- Language :
- English
- Volume :
- 10
- Database :
- OpenAIRE
- Journal :
- eLife
- Accession number :
- edsair.doi.dedup.....c2cce76d193819d92ea22ce8e7639fdc