Journal article
The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD+ Cleavage Activity that Promotes Pathological Axonal Degeneration
Neuron (Cambridge, Mass.), Vol.93(6), pp.1334-1343.e5
03/22/2017
DOI: 10.1016/j.neuron.2017.02.022
PMCID: PMC6284238
PMID: 28334607
Abstract
Axonal degeneration is an early and prominent feature of many neurological disorders. SARM1 is the central executioner of the axonal degeneration pathway that culminates in depletion of axonal NAD+, yet the identity of the underlying NAD+-depleting enzyme(s) is unknown. Here, in a series of experiments using purified proteins from mammalian cells, bacteria, and a cell-free protein translation system, we show that the SARM1-TIR domain itself has intrinsic NADase activity—cleaving NAD+ into ADP-ribose (ADPR), cyclic ADPR, and nicotinamide, with nicotinamide serving as a feedback inhibitor of the enzyme. Using traumatic and vincristine-induced injury models in neurons, we demonstrate that the NADase activity of full-length SARM1 is required in axons to promote axonal NAD+ depletion and axonal degeneration after injury. Hence, the SARM1 enzyme represents a novel therapeutic target for axonopathies. Moreover, the widely utilized TIR domain is a protein motif that can possess enzymatic activity.
•SARM1-TIR cleaves NAD+ into Nam, ADPR, and cADPR•SARM1 NADase activity is necessary for pathological axon loss•SARM1 is the first member of a new class of NADase enzyme•TIR domains can possess enzymatic activity
Essuman et al. demonstrate that the TIR domain of SARM1 is an enzyme that depletes axonal NAD+ to induce pathological axon loss. This enzymatic activity represents a novel therapeutic target for many neurological conditions characterized by axonal degeneration. More broadly, this study shows that TIR domains can possess enzymatic function.
Details
- Title: Subtitle
- The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD+ Cleavage Activity that Promotes Pathological Axonal Degeneration
- Creators
- Kow Essuman - Department of Genetics, Washington University School of Medicine, St. Louis, Missouri 63110, USADaniel W Summers - Department of Genetics, Washington University School of Medicine, St. Louis, Missouri 63110, USAYo Sasaki - Department of Genetics, Washington University School of Medicine, St. Louis, Missouri 63110, USAXianrong Mao - Department of Genetics, Washington University School of Medicine, St. Louis, Missouri 63110, USAAaron DiAntonio - Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri 63110, USAJeffrey Milbrandt - Department of Genetics, Washington University School of Medicine, St. Louis, Missouri 63110, USA
- Resource Type
- Journal article
- Publication Details
- Neuron (Cambridge, Mass.), Vol.93(6), pp.1334-1343.e5
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.neuron.2017.02.022
- PMID
- 28334607
- PMCID
- PMC6284238
- ISSN
- 0896-6273
- eISSN
- 1097-4199
- Grant note
- DOI: 10.13039/100000002, name: National Institutes of Health, award: RO1NS065053, RO1AG013730, RO1NS087632; DOI: 10.13039/100005202, name: Muscular Dystrophy Association, award: MDA349925; DOI: 10.13039/100000011, name: Howard Hughes Medical Institute; DOI: 10.13039/100005202, name: Muscular Dystrophy Association; name: Washington University Proteomics Shared Resource; name: Washington University Institute of Clinical and Translational Sciences, award: NCATS UL1 TR000448; name: Washington University Mass Spectrometry Research Resource, award: NIGMS P41 GM103422; name: Siteman Comprehensive Cancer Center, award: NCI P30 CA091842
- Language
- English
- Date published
- 03/22/2017
- Academic Unit
- Iowa Neuroscience Institute; Biology
- Record Identifier
- 9983991978102771
Metrics
30 Record Views