# Spatial Restriction of Apoptotic Machinery during Neuronal Apoptosis and Pruning

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2022 · $382,781

## Abstract

Project Summary/Abstract
 Neurons are capable of activating pathways that induce either the degeneration of the entire cell by
apoptosis or to selectively degenerate only the axons by pruning. While the main components of the caspase
activating machinery during apoptosis and pruning have been identified, a fundamental question of whether
the apoptotic machinery is activated throughout the neuronal soma and axons, or is spatially restricted, during
these events remains unknown. This question is most relevant in the context of pruning where one predicts the
apoptotic machinery to be localized to the targeted axons undergoing degeneration. However, we were
surprised to find an unexpected spatial restriction of caspase activation even during apoptosis, where we found
these to be restricted primarily to the soma, even though both soma and axons degenerate.
 In this proposal, we will mechanistically examine the spatial localization of the apoptotic machinery in
neurons during apoptosis and pruning. We will utilize neurons cultured in microfluidic chamber devices to
allow for the spatial segregation and manipulation of neuronal somas and axons. Our hypothesis is that during
apoptosis and pruning, the restricted caspase activity causes the “physiological axotomy” of axons, activating
the Sarm1-mediated axotomy pathway of axon degeneration. The concept that the developmental pathways of
apoptosis and pruning can cause axotomy is novel because these pathways were considered to be distinct from
the injury-induced axotomy pathway.
 In Aim 1, we will define the spatial restriction of the apoptotic machinery in neurons during apoptosis and
axon pruning. In Aim 2, we focus on examining the function of Sarm1 during apoptosis and axon pruning. In
Aim 3, we will investigate the Sarm1-deficient mice for pruning defects in vivo and evaluate if these mice
exhibit behavioral deficits. This project opens exciting areas of research not only because of its new concepts
for apoptosis and pruning, but also because it brings into focus a developmental function of Sarm1 that is
beyond its recognized role in axon injury.

## Key facts

- **NIH application ID:** 10417219
- **Project number:** 5R01NS122399-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Mohanish P Deshmukh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $382,781
- **Award type:** 5
- **Project period:** 2021-06-03 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10417219

## Citation

> US National Institutes of Health, RePORTER application 10417219, Spatial Restriction of Apoptotic Machinery during Neuronal Apoptosis and Pruning (5R01NS122399-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10417219. Licensed CC0.

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