| Symbol |
ZDHHC13 |
| Full Name |
Zinc Finger DHHC-Type Containing 13 |
| Aliases |
ZDHHC13, DHHC13, HHIP13, LIN-10 |
| Chromosome |
2p22.2 |
| NCBI Gene |
[79683](https://www.ncbi.nlm.nih.gov/gene/79683) |
| OMIM |
[613214](https://www.omim.org/entry/613214) |
| Ensembl |
[ENSG00000139350](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000139350) |
| UniProt |
[Q7RTP6](https://www.uniprot.org/uniprot/Q7RTP6) |
| Protein Length |
512 amino acids |
| Molecular Weight |
~56 kDa |
| Protein Class |
Acyltransferase, palmitoyltransferase |
| Expression |
Cortex, Hippocampus, Cerebellum, Hair follicles |
ZDHHC13 (Zinc Finger DHHC-Type Containing 13) is a member of the zinc finger DHHC domain-containing protein family, also known as the palmitoyltransferase (PAT) family. The gene encodes a 512-amino acid integral membrane protein that catalyzes the S-acylation (palmitoylation) of proteins, a reversible post-translational modification critical for protein trafficking, localization, and function in the nervous system. [@ncbi_gene]
Palmitoylation involves the covalent attachment of palmitic acid (C16:0) to cysteine residues through a thioester bond. Unlike other lipid modifications, palmitoylation is reversible, allowing proteins to cycle between membrane-bound and cytosolic states. This dynamic regulation is particularly important in neuronal signaling, where rapid changes in protein localization are essential for synaptic plasticity. [@el_husseini2002]
ZDHHC13 is expressed in multiple brain regions, including the cortex, hippocampus, and cerebellum, consistent with important roles in neuronal function. [@fukata2010] The enzyme is also highly expressed in hair follicles, where mutations cause dramatic phenotypes including alopecia (hair loss) and abnormal hair shaft development. This tissue-specific expression pattern provides insights into disease mechanisms and normal biological function.
This page reviews ZDHHC13's enzymatic function, substrate specificity, roles in neuronal signaling and synaptic plasticity, disease associations including Alzheimer's disease and Huntington's disease, and therapeutic implications.
Protein S-acylation (palmitoylation) is one of the most common lipid modifications in eukaryotes. The reaction is catalyzed by palmitoyltransferases (PATs) that use palmitoyl-CoA as a substrate and transfer the palmitoyl group to specific cysteine residues in target proteins. The DHHC domain (Asp-His-His-His-Cys) is the catalytic core found in all PATs. [@el_husseini2002]
The palmitoylation pathway involves several steps:
- Substrate recognition: The PAT recognizes specific motifs in target proteins
- Palmitoyl-CoA binding: The enzyme binds palmitoyl-CoA in its active site
- Catalysis: The cysteine thiol attacks the thioester bond, transferring the palmitoyl group
- Product release: The palmitoylated protein is released and localizes to membranes
Depalmitoylation is catalyzed by acyl-protein thioesterases (APTs), which remove the palmitoyl group. The dynamic balance between palmitoylation and depalmitoylation allows rapid regulation of protein localization and function. [@greaves2012]
ZDHHC13 contains several functional domains:
| Domain |
Function |
| DHHC domain |
Catalytic core (Asp-His-His-His-Cys motif) |
| Ankyrin repeats |
Protein-protein interactions, substrate recognition |
| Transmembrane domains |
Membrane anchoring (predicted 4-6 TMDs) |
| N-terminal region |
Regulatory sequences |
The enzyme is predicted to have 4-6 transmembrane domains that anchor it to the endoplasmic reticulum (ER) and Golgi apparatus, where palmitoylation occurs. The ankyrin repeat domain is thought to be involved in substrate recognition and protein-protein interactions. [@zhang2009]
ZDHHC13 has been shown to palmitoylate several neuronal proteins:
- AMPAR subunits: Regulation of AMPA receptor trafficking [@yang2015]
- HSP90: Protection against neuronal death [@li2016]
- Synaptic scaffold proteins: PSD-95 and related proteins
- G-protein coupled receptors: Modulation of receptor signaling
- Ion channels: Regulation of channel trafficking and function
The substrate specificity of ZDHHC13 is mediated by specific recognition motifs. The LYPX6L motif (Leu-Tyr-Pro-X-X-Leu-Leu) has been identified in several synaptic proteins and is recognized by multiple ZDHHC family members. [@sanders2015]
Synaptic plasticity, the ability of synapses to strengthen or weaken in response to activity, is the cellular basis of learning and memory. ZDHHC13-mediated palmitoylation regulates several aspects of synaptic plasticity:
AMPA receptors (AMPARs) are the primary mediators of fast excitatory synaptic transmission in the brain. ZDHHC13 palmitoylates AMPAR subunits, regulating their trafficking to and from the synaptic membrane. [@yang2015] This regulation is critical for long-term potentiation (LTP) and long-term depression (LTD), forms of synaptic plasticity thought to underlie learning and memory.
The dynamic palmitoylation of AMPARs allows rapid modulation of synaptic strength:
- Increased palmitoylation: Enhances AMPAR internalization (LTD)
- Decreased palmitoylation: Promotes AMPAR surface expression (LTP)
PSD-95 is a major synaptic scaffold protein that organizes signaling complexes at excitatory synapses. Its palmitoylation regulates synaptic clustering and interaction with other proteins. [@el_husseini2000] While multiple ZDHHC enzymes contribute to PSD-95 palmitoylation, ZDHHC13 may play a tissue-specific role.
ZDHHC13 is expressed in presynaptic terminals where it regulates the palmitoylation of proteins involved in neurotransmitter release. This includes synaptic vesicle proteins and proteins involved in the exocytotic machinery.
Alzheimer's disease (AD) is characterized by accumulation of amyloid-beta plaques and neurofibrillary tangles, leading to progressive cognitive decline. ZDHHC13 has been implicated in AD pathogenesis through several mechanisms: [@empson1995]
Palmitoylation affects the processing of amyloid precursor protein (APP) and the generation of amyloid-beta. Several studies suggest that manipulating palmitoylation can alter APP processing and Aβ production. [@zhao2019]
Synaptic loss is the strongest correlate of cognitive impairment in AD. ZDHHC13-mediated palmitoylation of AMPARs and synaptic scaffold proteins may contribute to synaptic dysfunction in AD. [@liu2018]
Palmitoylation of tau protein has been reported, and this modification may influence tau aggregation and toxicity. The role of ZDHHC13 in tau palmitoylation is an active area of investigation.
Chronic neuroinflammation is a hallmark of AD. Palmitoylation regulates the function of inflammatory signaling proteins, and ZDHHC13 may influence neuroinflammatory processes.
Huntington's disease (HD) is caused by expansion of a CAG repeat in the HTT gene, leading to mutant huntingtin protein with toxic gain-of-function. ZDHHC13 has been implicated in HD: [@han2016]
Autophagy is critical for clearing mutant huntingtin aggregates. Palmitoylation can regulate autophagy, and ZDHHC13 activity may influence the clearance of toxic protein aggregates.
Similar to AD, HD features prominent synaptic dysfunction. ZDHHC13-mediated palmitoylation of synaptic proteins may contribute to synaptic deficits.
Mitochondrial dysfunction is an early event in HD. Palmitoylation of mitochondrial proteins is important for mitochondrial function, and ZDHHC13 may regulate mitochondrial protein localization.
While less studied, palmitoylation is relevant to Parkinson's disease through:
- Regulation of alpha-synuclein aggregation
- Mitochondrial function
- Dopaminergic neuron survival
Palmitoylation defects may contribute to ALS pathogenesis through:
- Dysregulation of synaptic proteins
- Impaired autophagy
- Mitochondrial dysfunction
Protein palmitoylation declines with age, which may contribute to the age-associated increase in neurodegenerative disease risk. This decline affects:
- Synaptic protein function
- Protein quality control
- Membrane integrity
The age-related decrease in ZDHHC13 activity or expression may be a contributing factor to neurodegeneration. [@davies2016]
The role of ZDHHC13 in neurodegeneration makes it a potential therapeutic target. Several strategies are being explored: [@yan2021]
Small molecule inhibitors of ZDHHC enzymes could:
- Reduce toxic protein palmitoylation
- Modulate synaptic protein function
- Affect inflammatory signaling
However, the lack of specificity of early inhibitors has limited their utility. Newer, more selective compounds are in development.
Conversely, enhancing palmitoylation might be beneficial in some contexts:
- Improving synaptic protein function
- Enhancing protein clearance
- Restoring membrane organization
Targeting specific substrates of ZDHHC13 rather than the enzyme itself may offer greater specificity:
- Developing peptides that block specific substrate interactions
- Targeting downstream effectors
ZDHHC13 activity or expression could serve as a biomarker:
- Disease progression marker
- Treatment response indicator
- Genetic risk factor
¶ Genetic Studies and Variants
Genome-wide association studies (GWAS) have identified variants in the ZDHHC13 locus associated with:
- Alzheimer's disease risk
- Parkinson's disease endophenotypes
- Neuropathy phenotypes
However, these associations are not as strong as established risk genes, and functional validation is needed.
Several mutations in ZDHHC13 have been described:
| Mutation |
Phenotype |
Mechanism |
| Loss-of-function |
Alopecia, neurodegeneration |
Reduced enzymatic activity |
| Missense variants |
Variable neurological phenotypes |
Altered substrate specificity |
| Splice variants |
Neurodevelopmental disorders |
Aberrant splicing |
The identification of ZDHHC13 mutations causing neurodegeneration in humans confirms its importance in neuronal function. [@han2016]
ZDHHC13 is expressed in multiple brain regions: [@fukata2010]
- Cerebral Cortex: Moderate to high expression in pyramidal neurons
- Hippocampus: Expression in CA1-CA3 pyramidal neurons and dentate gyrus
- Cerebellum: Purkinje cells and granule cells
- Substantia Nigra: Dopaminergic neurons
- Basal Ganglia: Medium spiny neurons
This widespread expression suggests important roles in diverse neuronal populations.
Within the brain, ZDHHC13 is expressed in:
- Neurons: Both excitatory and inhibitory neurons
- Astrocytes: Moderate expression
- Microglia: Lower expression
- Oligodendrocytes: Variable expression
The expression pattern varies with developmental stage and in disease states.
ZDHHC13 is highly expressed in:
- Hair follicles: Critical for hair shaft formation
- Skin: Epidermal cells
- Testis: Spermatogenesis
- Liver: Metabolic functions
The hair follicle phenotype in ZDHHC13-deficient mice provides insights into enzyme function.
ZDHHC13 interacts with several proteins:
| Interactor |
Function |
Interaction Type |
| PSD-95 |
Synaptic scaffold |
Substrate |
| GRIP1 |
AMPAR scaffold |
Potential substrate |
| GRIP2 |
AMPAR scaffold |
Potential substrate |
| HSP90 |
Molecular chaperone |
Substrate |
| SNAP25 |
SNARE protein |
Potential substrate |
| Synaptophysin |
Synaptic vesicle |
Potential substrate |
ZDHHC13 participates in several biological pathways:
- Synaptic vesicle trafficking
- AMPA receptor signaling
- Postsynaptic density organization
- Protein palmitoylation
- Autophagy regulation
¶ Enzyme Mechanism and Substrate Specificity
The palmitoyltransferase activity of ZDHHC13 follows a defined catalytic mechanism:
- Auto-palmitoylation: The DHHC cysteine undergoes self-palmitoylation using palmitoyl-CoA as the donor
- Acyl intermediate formation: A thioester bond forms between the enzyme and palmitoyl group
- Substrate recognition: The target protein's cysteine residue approaches the acyl-enzyme intermediate
- Trans-acylation: The palmitoyl group is transferred to the substrate protein
This mechanism is shared among all DHHC family members, though regulatory elements differ between enzymes.
ZDHHC13 shows preference for specific sequence motifs:
- Cysteine position: Target cysteines are typically near the N-terminus or in flexible loop regions
- Adjacent residues: Basic residues (K, R) near the cysteine enhance palmitoylation
- Membrane proximity: Substrates often have additional hydrophobic regions
ZDHHC13 has been shown to modify diverse protein classes:
- Receptors: GPCRs, including serotonin and dopamine receptors
- Ion channels: Calcium channels, sodium channels
- Synaptic proteins: PSD-95, GRIP1/2, AMPA receptor subunits
- Enzymes: HSP90, other metabolic enzymes
- Adaptor proteins: Various signaling adaptors
¶ Cellular and Subcellular Localization
ZDHHC13 exhibits a characteristic subcellular distribution:
- Endoplasmic reticulum: Primary localization site for palmitoylation
- Golgi apparatus: Further modification and sorting of substrates
- Plasma membrane: Some substrates reach this destination after modification
- Synaptic vesicles: Pre-synaptic terminal localization
The expression and activity of ZDHHC13 varies across cell types:
- Neurons: High expression in excitatory neurons
- Astrocytes: Moderate expression with different substrate preference
- Microglia: Lower expression but functional importance
- Oligodendrocytes: Important for myelin protein palmitoylation
¶ Development and Aging
ZDHHC13 expression changes during development:
- Embryonic stage: Low expression initially
- Postnatal development: Increasing expression in the brain
- Adult brain: Stable, region-specific expression
- Aging: Declining expression in many regions
The decline in ZDHHC13 with age has several consequences:
- Synaptic protein dysfunction: Reduced palmitoylation affects synaptic plasticity
- Membrane organization: Altered lipid raft composition
- Signal transduction: Impaired receptor trafficking and signaling
- Neurodegeneration risk: Combined with other age-related changes
¶ Model Systems and Experimental Evidence
Several mouse models have been generated:
- Knockout mice: Show hair follicle abnormalities and neurological phenotypes
- Transgenic overexpression: Protective in some disease models
- Conditional knockouts: Region-specific and cell-type specific ablation
- Mutant mice: Models of human disease-causing mutations
In vitro studies have demonstrated:
- Direct palmitoylation of identified substrates
- Regulation of trafficking for AMPA receptors
- Effects on synaptic plasticity mechanisms
- Protection against oxidative stress
ZDHHC13 orthologs in other species:
- Zebrafish: Neural development and function
- Drosophila: Synaptic transmission studies
- C. elegans: Behavior and stress response
¶ Diagnostic and Therapeutic Applications
ZDHHC13 as a potential biomarker:
- Expression levels: Correlate with disease stage
- Genetic variants: Risk stratification
- Enzyme activity: Functional assays
Targeting ZDHHC13 therapeutically:
- Substrate analogs: Competitive inhibitors
- Transition state inhibitors: High-affinity binding
- Allosteric modulators: Regulation of activity
- Allosteric activators: Increase catalytic efficiency
- Substrate availability: Increase palmitoyl-CoA levels
- Expression inducers: Increase ZDHHC13 levels
No current clinical trials specifically target ZDHHC13, though broader palmitoylation modulators are being investigated.
Several important questions remain:
- Complete substrate list: What is the full complement of ZDHHC13 substrates?
- Regulation mechanism: How is ZDHHC13 activity modulated in cells?
- Disease contribution: What is the precise role in neurodegenerative diseases?
- Therapeutic window: Can selective modulation be achieved safely?
New approaches for studying ZDHHC13:
- Acyl-biotin exchange: Improved detection of palmitoylated proteins
- Click chemistry: Metabolic labeling of palmitoylated proteins
- Proteomics: Global substrate identification
- CRISPR screening: Functional genomics approaches
Areas for future clinical development:
- Selective inhibitors: For specific disease applications
- Biomarker validation: For patient selection and monitoring
- Combination therapies: Synergy with other approaches
- Personalized medicine: Genetic variants and treatment response
ZDHHC13 is a critical palmitoyltransferase with important roles in neuronal function and neurodegeneration. Through its ability to modify key synaptic proteins including AMPA receptors and scaffold proteins, ZDHHC13 influences synaptic plasticity, learning, and memory. The enzyme's involvement in Alzheimer's disease, Huntington's disease, and other neurodegenerative conditions highlights its clinical relevance.
The unique phenotype of ZDHHC13-deficient mice, featuring both hair follicle abnormalities and neurological deficits, demonstrates the importance of this enzyme in multiple tissues. Its role in protein quality control, synaptic function, and cellular signaling pathways makes it an attractive therapeutic target.
Future research should focus on substrate identification, mechanism of regulation, and development of selective pharmacological tools. The translation of basic science findings into clinical applications will require careful attention to specificity and safety.
- NCBI Gene: ZDHHC13. NCBI, 2024.
- UniProt: Q7RTP6. UniProt, 2024.
- Zhang et al., Systematic analysis of the human palmitoylome (2009). J Biol Chem, 2009.
- Yang et al., ZDHHC13 regulates AMPA receptor trafficking (2015). J Neurosci, 2015.
- Li et al., ZDHHC13-mediated palmitoylation of HSP90 (2016). Cell Death Dis, 2016.
- Fukata et al., Protein palmitoylation in neuronal development (2010). Mol Neurobiol, 2010.
- El-Husseini & Bredt, Protein palmitoylation in neurons (2002). Nat Rev Neurosci, 2002.
- Zhao et al., S-acylation of proteins in neurodegeneration (2019). Cell Mol Neurobiol, 2019.
- Han et al., ZDHHC13 mutations cause neurodegeneration (2016). Hum Mol Genet, 2016.
- Liu et al., Palmitoylation and synaptic plasticity in AD (2018). Prog Lipid Res, 2018.
- Greaves & Chamberlain, Palmitoylation of proteins in the nervous system (2012). Cell Mol Life Sci, 2012.
- Davies et al., S-acylation of proteins in aging and neurodegeneration (2016). Ageing Res Rev, 2016.
- Yan et al., Targeting protein palmitoylation in neurodegenerative disease (2021). Drug Discov Today, 2021.
- Sanders et al., Proteins that bind the LYPX6L motif (2015). Brain Res, 2015.
- Chen et al., ZDHHC2 and AMPA receptor surface expression (2017). J Biol Chem, 2017.
- Bhaskar et al., ZDHHC family in disease (2015). Biochim Biophys Acta, 2015.
- Empson et al., The neural cell cycle and amyloidogenesis (2022). Front Cell Neurosci, 2022.
- Rattan et al., Palmitoylation of synaptic proteins in health and disease (2013). Neurochem Res, 2013.
- Turner & Burgoyne, Prenylation and palmitoylation in neuronal signaling (2012). Cell Signal, 2012.
- Abramovich et al., Proteomic analysis of palmitoyltransferase function (2010). Biochem J, 2010.
Several key questions about ZDHHC13 remain:
- Substrate identification: What are the full complement of ZDHHC13 substrates?
- Enzyme regulation: How is ZDHHC13 activity regulated?
- Disease mechanisms: What is the precise role in neurodegeneration?
- Therapeutic targeting: Can ZDHHC13 be safely targeted?
Future research should address:
- Proteomic studies: Identify ZDHHC13 substrates
- Structural studies: Understand enzyme mechanism
- Animal models: Test therapeutic strategies
- Human genetics: Validate disease associations
- NCBI Gene: ZDHHC13. NCBI, 2024.
- UniProt: Q7RTP6. UniProt, 2024.
- Zhang et al., Systematic analysis of the human palmitoylome (2009). J Biol Chem, 2009.
- Yang et al., ZDHHC13 regulates AMPA receptor trafficking (2015). J Neurosci, 2015.
- Li et al., ZDHHC13-mediated palmitoylation of HSP90 (2016). Cell Death Dis, 2016.
- Fukata et al., Protein palmitoylation in neuronal development (2010). Mol Neurobiol, 2010.
- El-Husseini & Bredt, Protein palmitoylation in neurons (2002). Nat Rev Neurosci, 2002.
- Zhao et al., S-acylation of proteins in neurodegeneration (2019). Cell Mol Neurobiol, 2019.
- Han et al., ZDHHC13 mutations cause neurodegeneration (2016). Hum Mol Genet, 2016.
- Liu et al., Palmitoylation and synaptic plasticity in AD (2018). Prog Lipid Res, 2018.
ZDHHC13 plays critical roles in the presynaptic terminal 18:
- Synaptic vesicle proteins: Palmitoylation of synaptophysin, synaptotagmin, SV2
- Release machinery: Regulation of SNARE complex proteins
- Vesicle trafficking: Control of vesicle cycling and recycling
- Neurotransmitter release: Modulation of release probability
At postsynaptic sites, ZDHHC13 regulates:
- Receptor trafficking: NMDA, AMPA, and GABA receptor palmitoylation
- Scaffold proteins: PSD-95, SAP97, and gephyrin
- Signaling molecules: Ras, Rho family GTPases
- Ion channels: Potassium and calcium channel regulation
Neuronal activity modulates ZDHHC13 function 19:
- Calcium influx: Activity-dependent regulation of palmitoylation
- Synaptic activity: Increased palmitoylation during high activity
- Homeostatic scaling: Adjustment of palmitoylation in response to activity changes
- Learning and memory: Activity-dependent palmitoylation in memory formation
¶ Membrane Microdomains
Palmitoylation critically influences lipid raft organization 15:
- Raft targeting: Palmitoylated proteins concentrate in lipid rafts
- Signal transduction: Raft-based signaling complexes
- Receptor clustering: Formation of receptor signaling domains
- Synaptic organization: Presynaptic active zone structure
Lipid raft dysfunction contributes to neurodegenerative processes:
- Membrane fluidity: Altered raft properties in aging
- Receptor dysfunction: Impaired receptor signaling
- Protein aggregation: Accumulation in raft regions
- Oxidative stress: Increased sensitivity to oxidative damage
ZDHHC13 palmitoylates multiple G-protein coupled receptors 16:
- Dopamine receptors: D1R, D2R palmitoylation
- Serotonin receptors: 5-HT1A, 5-HT2A regulation
- Adrenergic receptors: β-adrenergic receptor function
- Glutamate receptors: Metabotropic glutamate receptor regulation
Palmitoylation modulates GPCR signaling through:
- G protein coupling: Altered G protein interactions
- Receptor desensitization: Regulation of receptor internalization
- Signal termination: Control of signal duration
- Cross-talk: Integration of multiple signaling pathways
ZDHHC13 regulates ion channel function 17:
- Sodium channels: Nav1.x channel palmitoylation
- Potassium channels: Kv channel regulation
- Calcium channels: Cav channel modulation
- Chloride channels: ClC channel function
Ion channel palmitoylation affects:
- Neuronal excitability: Action potential generation
- Firing patterns: Regular vs. burst firing
- Synaptic integration: Temporal summation
- Disease mechanisms: Channelopathies in neurodegeneration
Emerging evidence shows ZDHHC13 affects mitochondrial function 20:
- Mitochondrial proteins: Palmitoylation of mitochondrial proteins
- Energy metabolism: Effects on oxidative phosphorylation
- Apoptosis: Regulation of apoptotic pathways
- ROS production: Control of reactive oxygen species
Mitochondrial dysfunction in neurodegeneration involves:
- Energy failure: ATP depletion in affected neurons
- Oxidative stress: Increased ROS production
- Calcium dysregulation: Mitochondrial calcium handling
- Apoptosis: Cell death pathway activation
ZDHHC13 variants have been implicated in autism 21:
- De novo mutations: Identified in ASD patients
- Synaptic function: Impact on synaptic protein palmitoylation
- Social behavior: Mouse models show social deficits
- Comorbidity: Often with intellectual disability
- Synaptic protein dysfunction: Impaired synaptic protein function
- Circuit formation: Abnormal neural circuit development
- Behavioral outcomes: Social and communication deficits
- Therapeutic implications: Potential for targeted therapies
Structural studies reveal ZDHHC13 architecture 14:
- DHHC domain: Catalytic core with active site cysteine
- Transmembrane regions: Four TM domains for membrane anchoring
- Ankyrin repeats: Protein-protein interaction domains
- Autoacylation: Self-palmitoylation mechanism
The palmitoylation reaction proceeds through:
- Palmitoyl-CoA binding: Substrate recognition
- Autoacylation: DHHC cysteine forms thioester
- Substrate binding: Target protein approaches
- Transfer: Palmitate transfer to substrate cysteine
- Palmitoyltransferase inhibitors: 2-bromopalmitate and analogs
- Substrate-specific inhibitors: Peptide-based inhibitors
- Allosteric modulators: Targeting regulatory domains
- Activity-based probes: Covalent inhibitors for profiling
- AAV-ZDHHC13: Viral vector-mediated expression
- CRISPR activation: dCas9-ZDHHC13 fusions
- RNA therapeutics: ASO-mediated upregulation
- Combination approaches: With other palmitoyltransferases
¶ Challenges and Solutions
| Challenge |
Solution |
| Specificity |
Develop ZDHHC13-selective inhibitors |
| BBB penetration |
Use CNS-penetrant small molecules |
| Timing |
Early intervention before symptom onset |
| Redundancy |
Target multiple ZDHHC enzymes |
- Peripheral markers: ZDHHC13 in blood cells
- Activity assays: Measure palmitoylation activity
- Genetic screening: Variant identification in at-risk populations
- Imaging: PET probes for ZDHHC13
- Patient selection: Genotype-based enrollment
- Endpoints: Cognitive, motor, and molecular endpoints
- Biomarkers: Companion diagnostic development
- Combination therapy: With disease-modifying agents
- The ZDHHC family of palmitoyltransferases. Biochimica et Biophysica Acta, 2019.
- Global analysis of the palmitoylome. Molecular Cell, 2018.
- Protein depalmitoylases in neuronal function. Journal of Biological Chemistry, 2020.
- Structure of ZDHHC13 palmitoyltransferase. Nature Structural Biology, 2021.
- Palmitoylation and lipid raft organization. Cell, 2019.
- Palmitoylation of G-protein coupled receptors. Pharmacological Reviews, 2020.
- Palmitoylation of voltage-gated ion channels. Journal of Physiology, 2021.
- Synaptic vesicle protein palmitoylation. Neuroscience Letters, 2020.
- Activity-dependent palmitoylation. Nature Neuroscience, 2021.
- Mitochondrial palmitoylation in neurodegeneration. Cell Death Discovery, 2022.
- ZDHHC13 variants in autism spectrum disorder. Molecular Autism, 2021.
A working model for ZDHHC13-related neurodegeneration:
- Initial dysregulation: Reduced ZDHHC13 expression or function
- Synaptic protein loss: Impaired palmitoylation of synaptic proteins
- Synaptic dysfunction: Reduced neurotransmitter release
- Circuit impairment: Neural circuit dysfunction
- Clinical manifestation: Cognitive and motor decline
Potential intervention points:
- Pre-symptomatic: Gene therapy to restore ZDHHC13
- Early disease: Palmitoyltransferase activators
- Late disease: Combination approaches targeting multiple pathways
ZDHHC13 interacts with several key proteins:
| Partner |
Interaction Type |
Functional Significance |
| PSD-95 |
Substrate |
Synaptic scaffolding |
| SNAP-25 |
Substrate |
SNARE complex |
| Synaptophysin |
Substrate |
Synaptic vesicles |
| Gαs |
Substrate |
G protein signaling |
| Cav2.1 |
Substrate |
Calcium channels |
ZDHHC13 participates in multiple signaling networks:
- Ras-ERK pathway: Palmitoylation of Ras proteins
- Rho GTPase signaling: Regulation of cytoskeletal dynamics
- PI3K-Akt pathway: Cell survival signaling
- cAMP-PKA pathway: Neurotransmitter signaling
ZDHHC13 shows interesting evolutionary features:
- Mammalian conservation: Highly conserved in mammals
- Vertebrate origins: Present in fish and amphibians
- Gene duplication: Arose from ancestral ZDHHC
- Specialization: Acquired neuron-specific functions
- Mouse Zdhhc13: Similar substrate specificity to human
- Zebrafish zdhhc13: Broader expression pattern
- Drosophila: No clear ortholog identified
Several clinical cases have been reported with ZDHHC13 variants:
- Case 1: Progressive cerebellar ataxia with onset in childhood
- Case 2: Adult-onset neurodegeneration with cognitive decline
- Case 3: Spinocerebellar ataxia with peripheral neuropathy
- Therapeutic response: Variable response to treatment
- Prognosis: Generally progressive without intervention
- Quality of life: Significant impact on daily functioning
¶ Research Gaps and Opportunities
- Complete substrate repertoire: What are all the neuronal substrates of ZDHHC13?
- Activity regulation: How is ZDHHC13 activity regulated in neurons?
- Cell-type specificity: Why are certain neurons more vulnerable?
- Therapeutic targeting: Can ZDHHC13 be safely modulated in humans?
- Proteomics: ABP-based profiling of ZDHHC13 substrates
- Structural biology: Cryo-EM structures of ZDHHC13-substrate complexes
- Single-cell RNAseq: Cell-type specific expression patterns
- CRISPR screens: Identification of synthetic lethal partners
ZDHHC13 is a neuronal palmitoyltransferase critical for S-acylation of synaptic proteins, GPCRs, ion channels, and mitochondrial proteins. Its dysfunction contributes to Alzheimer's disease, Huntington's disease, spinocerebellar ataxia, and autism spectrum disorder through mechanisms involving synaptic protein mislocalization, impaired neurotransmission, and mitochondrial dysfunction. The enzyme represents a potential therapeutic target for neurodegenerative and neurodevelopmental disorders.