Publication Date:
2015-04-25
Description:
Axon degeneration is an intrinsic self-destruction program that underlies axon loss during injury and disease. Sterile alpha and TIR motif-containing 1 (SARM1) protein is an essential mediator of axon degeneration. We report that SARM1 initiates a local destruction program involving rapid breakdown of nicotinamide adenine dinucleotide (NAD(+)) after injury. We used an engineered protease-sensitized SARM1 to demonstrate that SARM1 activity is required after axon injury to induce axon degeneration. Dimerization of the Toll-interleukin receptor (TIR) domain of SARM1 alone was sufficient to induce locally mediated axon degeneration. Formation of the SARM1 TIR dimer triggered rapid breakdown of NAD(+), whereas SARM1-induced axon destruction could be counteracted by increased NAD(+) synthesis. SARM1-induced depletion of NAD(+) may explain the potent axon protection in Wallerian degeneration slow (Wld(s)) mutant mice.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4513950/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4513950/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gerdts, Josiah -- Brace, E J -- Sasaki, Yo -- DiAntonio, Aaron -- Milbrandt, Jeffrey -- F31 NS074517/NS/NINDS NIH HHS/ -- F31NS074517/NS/NINDS NIH HHS/ -- R01 AG013730/AG/NIA NIH HHS/ -- R01 DA020812/DA/NIDA NIH HHS/ -- R01 NS065053/NS/NINDS NIH HHS/ -- R01 NS078007/NS/NINDS NIH HHS/ -- R01 NS087632/NS/NINDS NIH HHS/ -- R01AG013730/AG/NIA NIH HHS/ -- R01DA020812/DA/NIDA NIH HHS/ -- R01NS065053/NS/NINDS NIH HHS/ -- R01NS078007/NS/NINDS NIH HHS/ -- R01NS087632/NS/NINDS NIH HHS/ -- New York, N.Y. -- Science. 2015 Apr 24;348(6233):453-7. doi: 10.1126/science.1258366. Epub 2015 Apr 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics, Washington University Medical School, Saint Louis, MO, USA. ; Department of Developmental Biology, Washington University Medical School, Saint Louis, MO, USA. ; Department of Developmental Biology, Washington University Medical School, Saint Louis, MO, USA. Hope Center for Neurological Disorders, Saint Louis, MO, USA. ; Department of Genetics, Washington University Medical School, Saint Louis, MO, USA. Hope Center for Neurological Disorders, Saint Louis, MO, USA. jmilbrandt@wustl.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25908823" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Armadillo Domain Proteins/chemistry/genetics/*metabolism
;
Axons/*metabolism/pathology
;
Cytoskeletal Proteins/chemistry/genetics/*metabolism
;
HEK293 Cells
;
Humans
;
Mice
;
Mice, Knockout
;
NAD/*metabolism
;
Neurons/metabolism/pathology
;
Peripheral Nerve Injuries/*metabolism
;
Protein Multimerization
;
Wallerian Degeneration/*metabolism/pathology
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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