ZDHHC17 Links S-Acylation, Huntington Disease, VCP-associated Multisystem Proteinopathy, and Amyotrophic Lateral Sclerosis.

Protein mislocalization is an important contributor to neurodegeneration. We have identified disrupted S-acylation as a driver of mislocalization. S-acylation, the addition of long-chain fatty acids to cysteine residues, is mediated by the ZDHHC family of S-acyltransferases, and regulates protein localization by modulating protein hydrophobicity. Among these enzymes, we have identified ZDHHC17 as a central node in neurodegenerative disease. Although decreased ZDHHC17 activity is correlated with Huntington disease (HD) pathology, its broader contributions to neurodegeneration remain poorly defined. Here, we present new evidence that ZDHHC17 S-acylates or interacts with multiple proteins implicated in amyotrophic lateral sclerosis (ALS), including Valosin-containing protein (VCP) and TAR DNA Binding Protein (TDP-43). We further confirm that VCP, TDP-43, and others (FUS, C9orf72, and SQSTM1) are S-acylated across rodent models of multiple neurodegenerative diseases, including Huntington Disease, VCP-associated multisystem proteinopathy, and ALS. Using biochemical acylation assays and confocal microscopy, we show that ZDHHC17 S-acylates VCP, depletes the nuclear localization of both VCP and TDP-43, and modulates VCP-dependent toxicity via ER-stress. Motivated by these findings, we investigated the functional significance of motor-neuronal (MN) ZDHHC17 by studying dHip14 (the fly analog of ZDHHC17) in Drosophila melanogaster. Here, we found that motor neuron-specific dHip14 knockdown (KD) in flies resulted in impaired motor ability, while ubiquitous deletion caused pharate adult lethality. Together, these results highlight a shared mechanism across neurodegenerative diseases. Collectively, our findings position ZDHHC17 as a critical enzyme that links fatty acylation, protein homeostasis, and neurodegeneration. Understanding how ZDHHC17 orchestrates S-acylation across different cellular pathways may reveal new therapeutic strategies to restore proteostasis in neurodegenerative disease.