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The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD+ Cleavage Activity that Promotes Pathological Axonal Degeneration

Neuron (Cambridge, Mass.), 2017-03, Vol.93 (6), p.1334-1343.e5 [Peer Reviewed Journal]

2017 Elsevier Inc. ;Copyright © 2017 Elsevier Inc. All rights reserved. ;Copyright Elsevier Limited Mar 22, 2017 ;ISSN: 0896-6273 ;EISSN: 1097-4199 ;DOI: 10.1016/j.neuron.2017.02.022 ;PMID: 28334607

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Title:
The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD+ Cleavage Activity that Promotes Pathological Axonal Degeneration
Author: Essuman, Kow ; Summers, Daniel W. ; Sasaki, Yo ; Mao, Xianrong ; DiAntonio, Aaron ; Milbrandt, Jeffrey
Subjects: Animals ; Armadillo Domain Proteins - genetics ; Armadillo Domain Proteins - metabolism ; axonal degeneration ; Axons - metabolism ; Axons - pathology ; Catalytic Domain ; Cells, Cultured ; Cleavage ; Cytokines ; Cytoskeletal Proteins - genetics ; Cytoskeletal Proteins - metabolism ; Enzymatic activity ; enzyme ; Enzymes ; Feedback ; Humans ; innate immunity ; Interleukin 1 ; Mammalian cells ; Metabolites ; Mice ; Mice, Knockout ; NAD ; NAD - metabolism ; NAD+ Nucleosidase - metabolism ; NADase ; Nerve Degeneration - metabolism ; Nerve Degeneration - pathology ; Neurodegeneration ; Neurological diseases ; Nicotinamide ; Peripheral neuropathy ; Proteins ; Ribose ; SARM1 ; TIR ; Toll/interleukin-1 receptor domain ; Traumatic brain injury ; Vincristine
Is Part Of: Neuron (Cambridge, Mass.), 2017-03, Vol.93 (6), p.1334-1343.e5
Description: 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.
Publisher: United States: Elsevier Inc
Language: English
Identifier: ISSN: 0896-6273
EISSN: 1097-4199
DOI: 10.1016/j.neuron.2017.02.022
PMID: 28334607
Source: Cell Press Free Archives
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The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD+ Cleavage Activity that Promotes Pathological Axonal Degeneration

2017 Elsevier Inc. ;Copyright © 2017 Elsevier Inc. All rights reserved. ;Copyright Elsevier Limited Mar 22, 2017 ;ISSN: 0896-6273 ;EISSN: 1097-4199 ;DOI: 10.1016/j.neuron.2017.02.022 ;PMID: 28334607

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