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

SUBMITTER: Essuman K 

PROVIDER: S-EPMC6284238 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature