# Regulation of Axonal Signaling by Palmitoylation

> **NIH NIH R01** · TEMPLE UNIV OF THE COMMONWEALTH · 2024 · $384,363

## Abstract

Project Summary
The long-term goal of this project is to define molecular mechanisms that govern the long distance transfer of
protein-based signals in axons. Retrograde (axon-to-soma) signals are critical to activate transcriptional
programs both during neurodevelopment and following nerve injury, while continuous anterograde (soma-to-
axon) supply of `axon survival factors' is essential to maintain distal axon integrity. We and others have found
that key proteins that convey these retrograde and anterograde signals are modified with the lipid palmitate,
which facilitates their trafficking on axonal vesicles. In particular, experiments in the first cycle of funding
revealed that retrograde signaling by Dual Leucine-zipper Kinase (DLK, an upstream activator (a `MAP3K') of
Mitogen-activated Protein Kinase (MAPK) pathways) critically requires palmitoylation. We now hypothesize
that palmitoylation more broadly controls several distinct aspects of axonal signaling. The first Aim will focus on
palmitoylation of JNK family MAPKs, which are key `effector' kinases downstream of DLK and other MAP3Ks.
We will determine whether palmitoylation of the neural-specific JNK3 is required for Wallerian degeneration of
distal axons, and whether JNK3 phosphorylates palmitoylated axon survival factors, triggering their
degradation via a novel phospho-dependent mechanism. Aim 2 will focus on Rap2, a novel palmitoylated
regulator that lies upstream of DLK, and will determine whether Rap2 and its palmitoylation are broadly
required for DLK-dependent retrograde signaling. Aim 3 will assess whether the unique reversibility of
palmitoylation, compared with other protein-lipid modifications, is used to facilitate `sushi belt transport'
whereby the key axon survival factor NMNAT2 undergoes palmitoylation-dependent anterograde trafficking on
vesicles and is then locally depalmitoylated to increase its enzymatic and axo-protective activity. The proposed
research will define new cellular and molecular roles for palmitoylation in axonal protein trafficking and
signaling and will provide key insights into how responses to axonal damage are coordinated and controlled.
Results of our study may also reveal broader principles of axonal protein transport and signaling, in turn
increasing our understanding of a range of neurodegenerative disorders in which these processes are
impaired.

## Key facts

- **NIH application ID:** 10902030
- **Project number:** 5R01NS094402-09
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** Gareth Thomas
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $384,363
- **Award type:** 5
- **Project period:** 2015-09-30 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10902030

## Citation

> US National Institutes of Health, RePORTER application 10902030, Regulation of Axonal Signaling by Palmitoylation (5R01NS094402-09). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10902030. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*