PUBLICATION
The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD+ Cleavage Activity that Promotes Pathological Axonal Degeneration
- Authors
- Essuman, K., Summers, D.W., Sasaki, Y., Mao, X., DiAntonio, A., Milbrandt, J.
- ID
- ZDB-PUB-200522-29
- Date
- 2017
- Source
- Neuron 93: 1334-1343.e5 (Journal)
- Registered Authors
- Keywords
- NAD(+), NADase, SARM1, TIR, Toll/interleukin-1 receptor domain, axonal degeneration, enzyme, innate immunity
- MeSH Terms
-
- Animals
- Armadillo Domain Proteins/genetics
- Armadillo Domain Proteins/metabolism*
- Axons/metabolism*
- Axons/pathology
- Catalytic Domain*
- Cells, Cultured
- Cytoskeletal Proteins/genetics
- Cytoskeletal Proteins/metabolism*
- Humans
- Mice
- Mice, Knockout
- NAD/metabolism*
- NAD+ Nucleosidase/metabolism*
- Nerve Degeneration/metabolism*
- Nerve Degeneration/pathology
- PubMed
- 28334607 Full text @ Neuron
Citation
Essuman, K., Summers, D.W., Sasaki, Y., Mao, X., DiAntonio, A., Milbrandt, J. (2017) The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD+ Cleavage Activity that Promotes Pathological Axonal Degeneration. Neuron. 93:1334-1343.e5.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping