Journal article
Sarm1-mediated axon degeneration requires both SAM and TIR interactions
The Journal of neuroscience, Vol.33(33), pp.13569-13580
08/14/2013
DOI: 10.1523/JNEUROSCI.1197-13.2013
PMCID: PMC3742939
PMID: 23946415
Abstract
Axon degeneration is an evolutionarily conserved pathway that eliminates damaged or unneeded axons. Manipulation of this poorly understood pathway may allow treatment of a wide range of neurological disorders. In an RNAi-based screen performed in cultured mouse DRG neurons, we observed strong suppression of injury-induced axon degeneration upon knockdown of Sarm1 [SARM (sterile α-motif-containing and armadillo-motif containing protein)]. We find that a SARM-dependent degeneration program is engaged by disparate neuronal insults: SARM ablation blocks axon degeneration induced by axotomy or vincristine treatment, while SARM acts in parallel with a soma-derived caspase-dependent pathway following trophic withdrawal. SARM is a multidomain protein that associates with neuronal mitochondria. Deletion of the N-terminal mitochondrial localization sequence disrupts SARM mitochondrial localization in neurons but does not alter its ability to promote axon degeneration. In contrast, mutation of either the SAM (sterile α motif) or TIR (Toll-interleukin-1 receptor) domains abolishes the ability of SARM to promote axonal degeneration, while a SARM mutant containing only these domains elicits axon degeneration and nonapoptotic neuronal death even in the absence of injury. Protein-protein interaction studies demonstrate that the SAM domains are necessary and sufficient to mediate SARM-SARM binding. SARM mutants lacking a TIR domain bind full-length SARM and exhibit strong dominant-negative activity. These results indicate that SARM plays an integral role in the dismantling of injured axons and support a model in which SAM-mediated multimerization is necessary for TIR-dependent engagement of a downstream destruction pathway. These findings suggest that inhibitors of SAM and TIR interactions represent therapeutic candidates for blocking pathological axon loss and neuronal cell death.
Details
- Title: Subtitle
- Sarm1-mediated axon degeneration requires both SAM and TIR interactions
- Creators
- Josiah Gerdts - Department of Genetics, Washington University School of Medicine, St. Louis, Missouri 63110, USADaniel W SummersYo SasakiAaron DiAntonioJeffrey Milbrandt
- Resource Type
- Journal article
- Publication Details
- The Journal of neuroscience, Vol.33(33), pp.13569-13580
- Publisher
- United States
- DOI
- 10.1523/JNEUROSCI.1197-13.2013
- PMID
- 23946415
- PMCID
- PMC3742939
- ISSN
- 1529-2401
- eISSN
- 1529-2401
- Grant note
- F31 NS074517 / NINDS NIH HHS 2T32CA9547-26 / NCI NIH HHS RF1 AG013730 / NIA NIH HHS R01 AG013730 / NIA NIH HHS AG013730 / NIA NIH HHS R01 NS078007 / NINDS NIH HHS NS078007 / NINDS NIH HHS T32 CA009547 / NCI NIH HHS NS074517 / NINDS NIH HHS R01 NS065053 / NINDS NIH HHS NS65053 / NINDS NIH HHS
- Language
- English
- Date published
- 08/14/2013
- Academic Unit
- Iowa Neuroscience Institute; Biology
- Record Identifier
- 9983991941202771
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