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Neuron. 2017 Mar 22;93(6):1334-1343.e5. doi: 10.1016/j.neuron.2017.02.022.

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

Author information

1
Department of Genetics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
2
Department of Genetics, Washington University School of Medicine, St. Louis, Missouri 63110, USA; Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
3
Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri 63110, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri 63110, USA. Electronic address: diantonio@wustl.edu.
4
Department of Genetics, Washington University School of Medicine, St. Louis, Missouri 63110, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri 63110, USA. Electronic address: jmilbrandt@wustl.edu.

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

PMID:
28334607
DOI:
10.1016/j.neuron.2017.02.022
[Indexed for MEDLINE]
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