Insights into SARM1’s Enzymatic Mechanisms for Executing Pathological Neuronal Death

The novel NAD + glycohydrolase, sterile alpha and toll/interleukin receptor (TIR) motif‐containing protein 1 (SARM1), is an active executioner in progressive axonal and neuronal degeneration. This type of degeneration, termed Wallerian degeneration, defines a number of diseases, including neuropathies, traumatic brain injury and neurodegenerative diseases. However, no therapies exist to mitigate these diseases. In fact, prior to the recent discovery of SARM1’s role in triggering Wallerian degeneration, the process was believed to occur passively. Stimulation of SARM1 activates its intrinsic NAD + hydrolase activity, resulting in NAD + cleavage and neuronal death. By contrast, knock down or knock out of SARM1 delays degeneration and has shown therapeutic efficacy for various Wallerian‐type diseases, including peripheral neuropathy and traumatic brain injury. NAD + supplementation alone is also sufficient to delay degeneration, indicating that inhibiting SARM1‐mediated NAD + hydrolysis would be efficacious. Thus, SARM1’s pivotal role in Wallerian degeneration makes it an attractive therapeutic target that could prevent disease progression. However, the design of therapeutics targeting SARM1 is limited by the dearth of knowledge surrounding its inherent NAD + hydrolase activity. Illuminating this black box has also been hindered by technical difficulties in obtaining pure active protein. Recently, we were able to purify active bacterially expressed protein, yielding insights into SARM1 morphology and cellular mechanism. Furthermore, we have performed detailed kinetic, catalytic and inhibitory studies, to determine SARM1’s kinetic and catalytic mechanisms and identify potential inhibitors to block SARM1‐mediated cell death. The results of these analyses will be discussed. Support or Funding Information NIH NINDS F31‐NS‐108610‐01