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

• Published in: Neuron (Cambridge, Mass.) Vol. 93; no. 6; pp. 1334 - 1343.e5
• Main Authors: Essuman, Kow, Summers, Daniel W., Sasaki, Yo, Mao, Xianrong, DiAntonio, Aaron, Milbrandt, Jeffrey
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.03.2017; Elsevier Limited
• 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; NAD; enzyme; innate immunity; SARM1; axonal degeneration; TIR; NADase; Toll/interleukin-1 receptor domain; NAD(+)
• ISSN: 0896-6273; 1097-4199; 1097-4199
• DOI: 10.1016/j.neuron.2017.02.022

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.