# Dissection of SARM1-Induced Axon Degeneration and Cell Death > **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $566,796 ## Abstract Project Summary/Abstract Programmed axon degeneration (AxD), a.k.a. Wallerian degeneration, is a genetically encoded cellular program akin to apoptosis by which neurons effect the orderly demolition of diseased or damaged axons. Our prior work demonstrated that the chief executioner of AxD, SARM1, is an NAD+ hydrolase allosterically regulated by NAD+ and its precursor NMN. SARM1 activation causes depletion of NAD+ that leads to local metabolic catastrophe and axon dissolution. SARM1-dependent AxD was primarily elucidated in models of acute injury that trigger all-or-none rapid axon loss, but we and others have also identified diverse conditions that provoke chronic SARM1 activation below the threshold necessary to provoke rapid AxD. Such subliminal SARM1 activity likely contributes to common neurodegenerative diseases including ALS, CMT2A and diabetic neuropathy. Our evidence indicates that this activity involves upstream and downstream molecular mechanisms that may not be engaged during canonical axotomy-induced Wallerian degeneration, mechanisms that impair axon resilience and contribute to compromised axon integrity and function in progressive neurodegenerative disorders. To enable the study of this subliminal SARM1 activity, we developed means to both manipulate and monitor the AxD pathway via titrating SARM1 activation and quantitatively measuring cADPR, a SARM1 activity biomarker. Here we use these tools to investigate the regulation of SARM1 by post-translational modification and the mechanisms by which DNA damage induces SARM1-dependent AxD. Our preliminary data show that SARM1 binds to and is ubiquitinated by Parkin in response to mitochondrial damage. We propose experiments to determine the unexplored impact of K63 regulatory ubiquitination on SARM1 activity. Such regulatory events are likely to impact chronic SARM1 activation and progressive disease. We will use kinase inhibitor panels to identify novel SARM1 regulators and employ a fluorescent SARM1 activity sensor and imaging-based screening technologies we recently developed to identify molecular components regulating SARM1 function by performing a CRISPR screen in models of subliminal SARM1 activation using gRNAs targeting all druggable genes including most kinases. We also find that disrupted cellular DNA repair activates SARM1-dependent AxD. DNA damage is associated with peripheral neuropathy in many neurodegenerative diseases including ALS and rare genetic disorders, as well as after chemotherapy. We will define the mechanisms of SARM1 activation due to DNA damage and how SARM1 promotes DNA damage-induced degeneration using human motor neuron models of ALS. Finally, our previous work led directly to development of therapeutic SARM1 inhibitors that are now in clinical development. Here we propose to develop therapeutic SARM1 activators as axon-specific neurolytics to treat localized chronic pain. In total, these studies will define mechanisms that regulate subliminal SARM1 activ... ## Key facts - **NIH application ID:** 10979975 - **Project number:** 2R01NS087632-11 - **Recipient organization:** WASHINGTON UNIVERSITY - **Principal Investigator:** Aaron Diantonio - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $566,796 - **Award type:** 2 - **Project period:** 2014-09-01 → 2029-05-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10979975 ## Citation > US National Institutes of Health, RePORTER application 10979975, Dissection of SARM1-Induced Axon Degeneration and Cell Death (2R01NS087632-11). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10979975. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*