PT  - JOURNAL ARTICLE
AU  - Heather S. Loring
AU  - Paul R. Thompson
TI  - A Liquid-to-Solid Phase Transition Enhances the Catalytic Activity of SARM1
AID  - 10.1101/2020.08.28.272377
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.08.28.272377
4099  - http://biorxiv.org/content/early/2020/08/29/2020.08.28.272377.short
4100  - http://biorxiv.org/content/early/2020/08/29/2020.08.28.272377.full
AB  - Sterile alpha and toll/interleukin receptor (TIR) motif–containing protein 1 (SARM1) is a neuronally expressed NAD+ glycohydrolase whose activity is increased in response to various stressors. The consequent depletion of NAD+ triggers axonal degeneration (i.e., Wallerian degeneration), which is a characteristic feature of neurological diseases, including peripheral neuropathies and traumatic brain injury. Notably, SARM1 knockout mice show minimal degeneration in models of peripheral neuropathy and traumatic brain injury, making SARM1 a promising therapeutic target. However, the development of SARM1 inhibitors has been challenging as the purified enzyme is largely inactive. Herein, we report that SARM1 activity is increased ∼2000–fold by a liquid-to-solid phase transition. These findings provide critical insights into SARM1 biochemistry with important implications for the situation in vivo. Moreover, they will facilitate the discovery of novel SARM1–targeted therapeutics.Competing Interest StatementThe authors have declared no competing interest.