# Palmitoylation-dependent Control of Glaucomatous Neurodegeneration

> **NIH NIH R21** · TEMPLE UNIV OF THE COMMONWEALTH · 2020 · $200,210

## Abstract

Project Summary / Abstract
A key factor in the neurodegenerative condition glaucoma is injury to axons in the optic nerve, which triggers
subsequent degeneration of Retinal Ganglion Cells (RGCs). Recent work has revealed a key role for Dual
Leucine-zipper Kinase (DLK), supported by DLK's close relative Leucine-zipper Kinase (LZK), in RGC
degeneration. There is therefore great interest in identifying DLK/LZK inhibitors to protect RGCs in glaucoma
and other neurodegenerative conditions. However, current strategies all seek to inhibit DLK/LZK's kinase
activity, an approach prone to undesired `off-target' effects due to the large number of similar kinases. We
recently found that DLK and LZK, but not homologous kinases, are covalently modified by the lipid palmitate.
Focusing on DLK, we have found that this process, palmitoylation, is essential for (i) DLK-dependent signaling
and (ii) DLK-dependent degeneration of RGC cell bodies 3 weeks after Optic Nerve Crush (ONC, a partial
model of glaucomatous injury) in vivo. These findings suggest that preventing DLK/LZK palmitoylation could be
as effective a therapeutic strategy as inhibition of DLK's kinase activity, while potentially minimizing off-target
issues. In this proposal we will first extend our preliminary findings to determine whether preventing DLK
palmitoylation (by replacement of endogenous DLK with a palmitoyl-site mutant) confers long-lasting protection
to RGCs after ONC in vivo. We will also determine whether specific loss of palmitoyl-DLK protects RGC axons
proximal to the injury site. In parallel studies we will assess the extent to which ZDHHC17, a Palmitoyl
Acyltransferase enzyme that controls DLK palmitoylation in cultured neurons, is essential for ONC-induced
RGC degeneration. We will determine whether a novel ZDHHC17 interaction motif in DLK is essential for DLK-
ZDHHC17 binding and for RGC degeneration by palmitoyl-DLK (Aim 1). In parallel studies, we will build on a
novel High Content Imaging Assay that we have recently optimized in order to screen for inhibitors of DLK
palmitoylation. Together with our Co-I Dr. Don Zack we will then determine whether inhibitors from this screen
can protect both mouse and human Embryonic Stem Cell-derived RGCs in a model of axonal injury that was
recently optimized by the Zack lab (Aim 2). Results from Aim 1 should provide new insights into mechanisms of
RGC degeneration, while Aim 2 may yield an entirely new class of neuroprotectants, with broad implications for
the treatment of glaucoma and perhaps other neurodegenerative conditions.

## Key facts

- **NIH application ID:** 9936337
- **Project number:** 5R21EY029386-02
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** Gareth Thomas
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $200,210
- **Award type:** 5
- **Project period:** 2019-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9936337

## Citation

> US National Institutes of Health, RePORTER application 9936337, Palmitoylation-dependent Control of Glaucomatous Neurodegeneration (5R21EY029386-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9936337. Licensed CC0.

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