@article{3feecc0a70a5446a9e7536b4c129cc85,
title = "The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD+ Cleavage Activity that Promotes Pathological Axonal Degeneration",
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.",
keywords = "NAD, NADase, SARM1, TIR, Toll/interleukin-1 receptor domain, axonal degeneration, enzyme, innate immunity",
author = "Kow Essuman and Summers, {Daniel W.} and Yo Sasaki and Xianrong Mao and Aaron DiAntonio and Jeffrey Milbrandt",
note = "Funding Information: This work was supported by the National Institutes of Health(grant RO1NS065053, to A.D.; grant RO1AG013730, to J.M.; and grant RO1NS087632, to J.M. and A.D.). and the Muscular Dystrophy Association grant MDA349925 (to A.D.). K.E. is a Howard Hughes Medical Institute Medical Research Fellow. D.W.S. is supported by a Development Grant from the Muscular Dystrophy Association (MDA344513). The protein identifications and LC-MS analyses were generated at the Washington University Proteomics Shared Resource (WU-PSR). WU-PSR is supported by the Washington University Institute of Clinical and Translational Sciences (NCATS UL1 TR000448), the Washington University Mass Spectrometry Research Resource (NIGMS P41 GM103422), and the Siteman Comprehensive Cancer Center (NCI P30 CA091842). Washington University, J.M., and Y.S. may derive income from licensing of technology to ChromaDex. We thank T. Fahrner and K. Simburger for technical assistance, and we thank members of the Milbrandt and DiAntonio labs for fruitful discussions. Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",
year = "2017",
month = mar,
day = "22",
doi = "10.1016/j.neuron.2017.02.022",
language = "English",
volume = "93",
pages = "1334--1343.e5",
journal = "Neuron",
issn = "0896-6273",
number = "6",
}