# Investigating the Activation Mechanism of SARM1 during Axon Degeneration

> **NIH NIH F31** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2022 · $31,506

## Abstract

PROJECT SUMMARY
 After injury, axons begin to die via a process that is characterized by axonal fragmentation and disintegration
of myelin sheath. This process is often termed Wallerian degeneration after Augustus Waller. Wallerian-like
degeneration, which is morphologically similar to Wallerian degeneration, is associated with the early stages of
many neurodegenerative diseases, including as Alzheimer’s, Huntington’s, and Parkinson’s Diseases. Wallerian
degeneration was long thought to occur passively, but the discovery of proteins that actively prevent or promote
degeneration negated this idea. One such protein is SARM1. SARM1 is a NAD+ hydrolase that cleaves NAD+ to
nicotinamide, ADPR, and cyclic ADPR; generation of these products ultimately leads to axonal degeneration.
Moreover, SARM1 knockout delays degeneration in animal models of Wallerian-like diseases, including
traumatic brain injury and peripheral neuropathy. Given the critical role of SARM1 in Wallerian-like diseases,
the central hypothesis of this proposal is that SARM1 inhibition would prevent the pathophysiology of axon
degeneration associated with neurodegenerative diseases. However, development of SARM1 inhibitors is limited
by the lack of knowledge surrounding the regulation, structure, and mechanism of this enzyme. As such, the goal
of this proposal is to understand SARM1 regulation in the context of Wallerian degeneration, and this goal will
be achieved by pursing the following Specific Aims. Aim 1 focuses on identifying proteins that regulate SARM1
activity. Proximity dependent labeling will also be used to identify proteins that interact with SARM1. The impact
of SARM1 interacting proteins on NAD+ hydrolase activity and SARM1-mediated axon degeneration will also be
assessed. These experiments will identify intermolecular events that regulate SARM1 during axon degeneration.
Aim 2 will focus on understanding the structure and function of TIR-1, the C. elegans ortholog of SARM1. Here,
we will solve the TIR-1 structure and characterize the enzymatic mechanism of this enzyme. These studies will
complement recent structural and kinetic studies of SARM1 and will yield insights into the intramolecular
characteristics of SARM1/TIR-1 that contribute to its degenerative capacity. Investigation into the regulation of
SARM1, both inter- and intramolecularly, is a rapidly growing field in the context of neurodegenerative diseases.
As such, completion of this work will significantly enhance our understanding of the fundamental molecular
mechanisms that control axonal degeneration. These studies will yield insights into the role of SARM1 in axon
degeneration, which will have broad implications in the development of therapeutics for neurodegenerative
diseases.

## Key facts

- **NIH application ID:** 10485170
- **Project number:** 5F31NS122423-02
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Janneke Doedee Icso
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $31,506
- **Award type:** 5
- **Project period:** 2021-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10485170

## Citation

> US National Institutes of Health, RePORTER application 10485170, Investigating the Activation Mechanism of SARM1 during Axon Degeneration (5F31NS122423-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10485170. Licensed CC0.

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