| ZDHHC8 — Zinc Finger DHHC-Type Palmitoyltransferase 8 | |
|---|---|
| Symbol | ZDHHC8 |
| Full Name | Zinc Finger DHHC-Type Palmitoyltransferase 8 |
| Chromosome | 22q11.21 |
| NCBI Gene | 57103 |
| Ensembl | ENSG00000140995 |
| OMIM | 611415 |
| UniProt | Q9NXK5 |
| Diseases | Schizophrenia, 22q11.2 Deletion Syndrome, Bipolar Disorder |
| Expression | Brain ([Cortex](/brain-regions/cortex), [Hippocampus](/brain-regions/hippocampus), Cerebellum), [Neurons](/entities/neurons) |
ZDHHC8 (Zinc Finger DHHC-Type Palmitoyltransferase 8) is a critical enzyme that catalyzes S-acylation (palmitoylation) of proteins, a reversible post-translational modification essential for protein trafficking, localization, and function in neurons. As a member of the zinc finger DHHC (Asp-His-His-Cys)-type containing protein family, ZDHHC8 plays a fundamental role in neuronal development, synaptic function, and neurotransmission. Notably, ZDHHC8 is located within the 22q11.2 chromosomal deletion region, one of the most common copy number variations in humans, which confers significant risk for schizophrenia, bipolar disorder, and other neurodevelopmental disorders.
Palmitoylation is unique among post-translational modifications due to its reversibility, allowing dynamic regulation of protein localization and function in response to cellular signals. This stands in contrast to other lipid modifications like myristoylation or prenylation, which are generally irreversible. The dynamic nature of palmitoylation makes it particularly important in neuronal signaling, where rapid changes in protein localization and function are required for synaptic plasticity, learning, and memory.
ZDHHC8 is located on chromosome 22q11.21, within the 22q11.2 deletion syndrome critical region. This location is significant because the 22q11.2 deletion, affecting approximately 1 in 4,000 live births, is one of the most common chromosomal deletion syndromes and includes ZDHHC8 as one of approximately 60-70 genes haploinsufficient in this region.
ZDHHC8 encodes a protein palmitoyltransferase containing several key structural features:
ZDHHC8 catalyzes palmitoylation through a two-step mechanism:
This reaction is reversible, with depalmitoylases (such as ABHD17A) catalyzing the reverse reaction, allowing dynamic control of protein palmitoylation status.
ZDHHC8 exhibits high expression in brain regions critical for cognition and emotion:
Within neurons, ZDHHC8 is primarily localized to:
ZDHHC8 palmitoylates numerous neuronal proteins:
ZDHHC8-mediated palmitoylation regulates:
ZDHHC8 is one of the genes within the 22q11.2 deletion region implicated in schizophrenia risk:
Genetic Evidence:
Mechanism:
Neurobiological Findings:
ZDHHC8 plays a central role in the neurodevelopmental phenotype of 22q11.2 deletion syndrome:
Phenotypic Features:
ZDHHC8 Contribution:
ZDHHC8 variants have been associated with bipolar disorder:
Autism Spectrum Disorder: Some evidence for ZDHHC8 involvement in ASD:
Epilepsy: Potential association with epilepsy risk:
ZDHHC8 represents a potential therapeutic target:
ZDHHC8 expression or activity could serve as:
ZDHHC8 knockout and transgenic models have been developed:
ZDHHC8 knockdown in zebrafish:
ZDHHC8 encodes a critical neuronal palmitoyltransferase that catalyzes the S-acylation of synaptic proteins essential for brain development and function. Located within the 22q11.2 deletion syndrome region, ZDHHC8 haploinsufficiency contributes significantly to the increased risk of schizophrenia and other psychiatric disorders in affected individuals. Through palmitoylation of PSD-95, SNAP-25, synaptophysin, and numerous other neuronal proteins, ZDHHC8 regulates synaptic organization, neurotransmitter release, and neural circuit formation. Understanding ZDHHC8 function provides insights into neurodevelopmental disorders and may lead to novel therapeutic approaches for treating schizophrenia and related conditions.