A Liquid-to-Solid Phase Transition Enhances the Catalytic Activity of SARM1

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.