| First Author | Essuman K | Year | 2017 |
| Journal | Neuron | Volume | 93 |
| Issue | 6 | Pages | 1334-1343.e5 |
| PubMed ID | 28334607 | Mgi Jnum | J:256058 |
| Mgi Id | MGI:6114587 | Doi | 10.1016/j.neuron.2017.02.022 |
| Citation | Essuman K, et al. (2017) The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD(+) Cleavage Activity that Promotes Pathological Axonal Degeneration. Neuron 93(6):1334-1343.e5 |
| abstractText | 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. |
