# Control of Axon Degeneration by Palmitoylation

> **NIH NIH F31** · TEMPLE UNIV OF THE COMMONWEALTH · 2024 · $34,104

## Abstract

PROJECT SUMMARY
Degeneration of neuronal axons is a hallmark of diverse neuropathological conditions, ranging from acute nerve
injuries to chronic neuropathies and neurodegenerative diseases. If we better understood the mechanisms of
axon degeneration, we could devise new therapies to potentially slow or prevent axon degeneration and
ameliorate a range of neuropathologies. Recent findings suggest that one key event in axon degeneration is the
loss of ‘axon survival factors’, labile proteins whose continuous supply from neuronal cell bodies to distal axons
normally ensures axon integrity. The damage to axons that occurs after injury, or in chronic neuropathies,
disrupts the supply of survival factors and triggers distal axon degeneration. The best-known axon survival factor,
nicotinamide mononucleotide adenylyl transferase-2 (NMNAT2) requires the protein-lipid modification
palmitoylation for its fast axonal transport, but how palmitoylation contributes to NMNAT2 degradation is not fully
clear. I identified previously unrecognized phosphorylation sites on NMNAT2, whose phosphorylation by c-Jun
N-terminal kinase (JNK) triggers selective degradation of palmitoyl-NMNAT2 in cultured cells. While addressing
this question, I also realized that several other regulators of axon degeneration are palmitoylated, in addition to
NMNAT2. Given that palmitoylation is the only reversible protein-lipid modification, I asked if acute
depalmitoylation of NMNAT2 and/or other axonal proteins is important for axon degeneration. My results
revealed that pharmacological inhibition of protein depalmitoylases indeed protects axons from degeneration
and additional preliminary genetic data ascribe this protection to block of a recently described depalmitoylase,
ABHD16A. However, axon protection by depalmitoylase inhibitors is independent of NMNAT2 and other known
axon survival factors, suggesting that additional protein(s) are depalmitoylated after axonal damage to drive
subsequent degeneration. The hypothesis that underlies this proposal is that palmitoylation plays broad,
previously unrecognized roles in the control of axon degeneration. Experiments in Aim 1 will use a recently
generated phospho-mutant knockin mouse to define the importance of phosphorylation by JNK for NMNAT2
degradation and subsequent axon degeneration, both in cultured neurons and in vivo. Aim 2A will determine
whether ABHD16A is indeed the key depalmitoylase whose activity is required for axon degeneration and will
provide the first cell biological characterization of ABHD16A localization in axons. In Aim 2B I will break new
ground by comprehensively identifying axonal proteins that are rapidly depalmitoylated after axonal injury, in
order to identify those protein(s) whose acute depalmitoylation drives axon degeneration. Together, the results
of these studies will provide new insights into the cell biology of axonal (de)palmitoylation, will define key events
that drive axon degeneration, and could reve...

## Key facts

- **NIH application ID:** 10997249
- **Project number:** 1F31NS135943-01A1
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** Natasha Louise Hesketh
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $34,104
- **Award type:** 1
- **Project period:** 2024-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10997249

## Citation

> US National Institutes of Health, RePORTER application 10997249, Control of Axon Degeneration by Palmitoylation (1F31NS135943-01A1). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10997249. Licensed CC0.

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