HDAC5 Gene
Introduction
Mermaid diagram (expand to render)
<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">HDAC5 Gene</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>HDAC5</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Histone Deacetylase 5</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>18q21.1</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>10014</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>605315</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000108840</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9UQL6</td>
</tr>
<tr>
<td class="label">Compound</td>
<td>Specificity</td>
</tr>
<tr>
<td class="label">Vorinostat</td>
<td>Pan-HDAC</td>
</tr>
<tr>
<td class="label">Entinostat (MS-275)</td>
<td>HDAC1/2/3</td>
</tr>
<tr>
<td class="label">PCI-34051</td>
<td>HDAC8</td>
</tr>
<tr>
<td class="label">5-azacytidine</td>
<td>DNAC/HDAC</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/carcinoma" style="color:#ef9a9a">Carcinoma</a>, <a href="/wiki/tumor" style="color:#ef9a9a">Tumor</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">39 edges</a></td>
</tr>
</table>
HDAC5 (Histone Deacetylase 5) is a Class IIa histone deacetylase that plays critical roles in epigenetic regulation, neuronal plasticity, and stress responses. It is implicated in the pathogenesis of Alzheimer's disease, Parkinson's disease, Huntington's disease, and other neurodegenerative disorders["@graff2013"][@haberland2009].
Gene Overview
Protein Structure
HDAC5 is a 1122-amino acid protein with distinct structural domains[@yang2003]:
Domain Architecture
N-terminal Regulatory Domain (1-421 aa): Contains binding sites for transcription factors including MEF2 (Myocyte Enhancer Factor 2), 14-3-3 chaperone proteins, and various signal-dependent kinases[@mckinsey2000]
Catalytic Domain (482-680 aa): Contains the zinc-dependent HDAC活性位点 responsible for histone deacetylase function
C-terminal Domain (682-1022 aa): Contains additional regulatory elements and nuclear localization/export signalsPost-translational Modifications
HDAC5 activity and localization are regulated by multiple phosphorylation events:
- Serine 259 and Serine 498: Phosphorylation by CaMK (Calcium/Calmodulin-dependent Kinase) creates 14-3-3 binding sites, promoting nuclear export[@grozinger2000]
- Serine 310: Phosphorylation by PKD (Protein Kinase D) regulates HDAC5 nuclear-cytoplasmic shuttling
- Lysine acetylation: Modulates HDAC5 transcriptional repressive activity
Biological Functions
Epigenetic Regulation
HDAC5 mediates epigenetic modifications through histone deacetylation[@kelly2023]:
- Histone deacetylation: Removes acetyl groups from lysine residues on histone tails (particularly H3 and H4), leading to chromatin condensation and transcriptional repression
- Non-histone substrates: Deacetylates transcription factors including p53, [NF-κB](/entities/nf-kb), and MEF2, modulating their activity and stability
- Chromatin remodeling complexes: Part of the Sin3A and NuRD co-repressor complexes
Neuronal Functions
In [neurons](/entities/neurons), HDAC5 regulates critical processes[@yamaguchi2023][@sando2012]:
Synaptic plasticity: Controls expression of plasticity-related genes including BDNF (Brain-Derived Neurotrophic Factor), c-Fos, and Arc
Memory formation: Hippocampal HDAC5 activity is essential for long-term memory consolidation and reconsolidation
Neuronal survival: Regulates anti-apoptotic gene expression and cellular stress responses
Dendritic arborization: Modulates actin cytoskeleton dynamics through MEF2-dependent transcriptionSignal Transduction
HDAC5 responds to various cellular signals[@chawla2003]:
- Calcium signaling: CaMK-mediated phosphorylation links neuronal activity to epigenetic changes
- cAMP/PKA signaling: Regulates HDAC5 nuclear export through PKA phosphorylation
- Growth factor signaling: BDNF and NGF signaling modulate HDAC5 activity and localization
Role in Neurodegenerative Diseases
Alzheimer's Disease
HDAC5 is prominently implicated in Alzheimer's disease pathogenesis[@volakakis2016][@marathe2018]:
Amyloid-β Pathology
- Amyloid-β oligomers induce HDAC5 nuclear export in hippocampal neurons
- This relocalization reduces BDNF expression and contributes to synaptic dysfunction
- HDAC5 dysfunction may impair amyloid clearance mechanisms
[Tau](/proteins/tau) Pathology
- HDAC5 interacts with tau phosphorylation dynamics through regulation of GSK3β and [CDK5](/proteins/cdk5) signaling
- Tau pathology is associated with altered HDAC5 nuclear-cytoplasmic distribution
Therapeutic Implications
- [HDAC](/entities/hdac-enzymes) inhibitors (particularly isoform-selective compounds) show cognitive enhancement in AD models
- HDAC5-specific modulators represent a promising therapeutic approach
- Challenge: achieving brain penetration while maintaining selectivity
Parkinson's Disease
HDAC5 dysregulation contributes to PD pathophysiology[@hu2022]:
- [α-Synuclein](/proteins/alpha-synuclein) toxicity: HDAC5 nuclear export is induced by α-synuclein aggregates
- Mitochondrial dysfunction: HDAC5 regulates PGC-1α expression, affecting mitochondrial biogenesis
- Dopaminergic neuron survival: HDAC5 activity protects dopaminergic neurons from oxidative stress
Huntington's Disease
HDAC5 is a therapeutic target in Huntington's disease[@bardai2019][@thomas2008]:
- Mutant [huntingtin](/proteins/huntingtin): Interacts with HDAC5 and alters its normal nuclear-cytoplasmic shuttling
- Transcriptional dysregulation: HDAC5 dysfunction contributes to the widespread transcriptional deficits observed in HD
- Therapeutic targeting: HDAC5 reduction or inhibition reduces mutant huntingtin toxicity in cellular and mouse models
Other Neurodegenerative Disorders
- Amyotrophic Lateral Sclerosis (ALS): HDAC5 regulates genes involved in motor neuron survival
- Frontotemporal Dementia (FTD): Altered HDAC5 expression in frontal [cortex](/brain-regions/cortex)
- Multiple Sclerosis: HDAC5 modulates neuroinflammation and demyelination
Expression Pattern
Brain Regional Distribution
HDAC5 shows region-specific expression[@broide2007]:
- High expression: Cerebral cortex (particularly layer 5), [hippocampus](/brain-regions/hippocampus) (CA1-CA3, dentate gyrus), basal ganglia (striatum, globus pallidus), cerebellum (Purkinje cells)
- Moderate expression: Thalamus, hypothalamus, brainstem nuclei
- Cellular localization: Both neuronal and glial expression; nuclear localization in resting neurons
Development
- Embryonic expression: Detectable from embryonic day 12 in mouse brain
- Postnatal development: Progressive increase during postnatal development
- Adult brain: Maintained expression throughout life, with activity-dependent nuclear-cytoplasmic shuttling
Therapeutic Target
HDAC Inhibitors
Current therapeutic approaches targeting HDAC5[@gray2023][@consalvi2023]:
Challenges
Isoform selectivity: Developing HDAC5-specific inhibitors vs. pan-HDAC or class IIa-selective compounds
[Blood-brain barrier](/entities/blood-brain-barrier): Achieving sufficient CNS penetration
Temporal targeting: Timing interventions to maximize therapeutic benefit
Biomarker development: Identifying patient selection criteriaInteracting Proteins
HDAC5 interacts with numerous proteins[@mihaylova2011]:
Transcription Factors
- MEF2A/D: Myocyte enhancer factor 2 family - major neuronal transcriptional regulators
- p53: Tumor suppressor - HDAC5 deacetylates p53, modulating its transcriptional activity
- NF-κB: Pro-inflammatory transcription factor - HDAC5 can repress NF-κB signaling
Co-repressor Complexes
- Sin3A complex: Corepressor complex mediating HDAC5-dependent transcription repression
- NuRD complex: Nucleosome remodeling and deacetylase complex
- CoREST complex: REST co-repressor complex
Signaling Proteins
- 14-3-3 proteins: Chaperone proteins that bind phosphorylated HDAC5
- CaMK isoforms: Calcium/calmodulin-dependent kinases phosphorylate HDAC5
- PKD: Protein kinase D
Research Methods
Experimental Approaches
Molecular biology: qPCR, Western blot, ChIP-seq for HDAC5 target identification
Cellular models: Primary neuron cultures, iPSC-derived neurons
Animal models: HDAC5 knockout mice, conditional knockouts, viral-mediated knockdown
Biochemistry: Co-immunoprecipitation, mass spectrometry for interacting proteinsBiomarkers
- HDAC5 expression: Measured by qPCR or immunohistochemistry in postmortem brain tissue
- Phosphorylation status: Detection of serine 259/498 phosphorylation
- Nuclear/cytoplasmic ratio: Indicator of HDAC5 activity state
See Also
- [HDAC5 Protein](/proteins/hdac5-protein)
- [Epigenetic Mechanisms in Neurodegeneration](/mechanisms/epigenetic-regulation)
- [Histone Acetylation](/mechanisms/histone-acetylation)
- [Transcription Factors in Neurodegeneration](/mechanisms/transcription-regulation)
- [Alzheimer's Disease Genes](/diseases/alzheimer-disease-genetics)
- [Parkinson's Disease Genes](/diseases/parkinson-disease-genetics)
External Links
- [NCBI Gene: hdac5](https://www.ncbi.nlm.nih.gov/gene/)
- [PubMed: hdac5](https://pubmed.ncbi.nlm.nih.gov/?term=hdac5+neurodegeneration)
References
[Graff J, Tsai LH, Histone acetylation: molecular mnemonics on chromatin (2013)](https://pubmed.ncbi.nlm.nih.gov/23225131/)
[Haberland M, Montgomery RL, Olson EN, The many roles of histone deacetylases in development and physiology: implications for disease and therapy (2009)](https://pubmed.ncbi.nlm.nih.gov/19065135/)
[Yang XJ, Seto E, The Rpd3/Hda1 family of histone deacetylases (2003)](https://pubmed.ncbi.nlm.nih.gov/12881426/)
[McKinsey TA, Zhang CL, Lu J, Olson EN, Signal-dependent nuclear export of a histone deacetylase regulates muscle differentiation (2000)](https://pubmed.ncbi.nlm.nih.gov/11081517/)
[Grozinger CM, Schreiber SL, Regulation of histone deacetylase 4 and 5 and transcriptional activity by 14-3-3-dependent cellular localization (2000)](https://pubmed.ncbi.nlm.nih.gov/10869435/)
[Kelly RD, Cowley SM, The physiological roles of histone deacetylase (HDAC) 1 and 2: complex co-stars with the leading cast (2023)](https://doi.org/10.3390/ijms24032684)
[Yamaguchi K, Lantowski A, Dannenberg JH, et al, Histone deacetylase 5 regulates neuronal differentiation and embryonic stem cell development (2023)](https://pubmed.ncbi.nlm.nih.gov/37067923/)
[Sando R 3rd, Gounko N, Pieraut S, et al, Regulation of dendritic branching and spine maturation by neuronal activity-dependent histone deacetylase 5 (2012)](https://pubmed.ncbi.nlm.nih.gov/23055506/)
[Chawla S, Vanhoutte P, Arnold FJ, Huang CL, Bading H, Nuclear calcium-activated histone deacetylase 5 represses transcriptional activity (2003)](https://pubmed.ncbi.nlm.nih.gov/12871581/)
[Volakakis N, Kadkhodaei B, Joodmardi E, et al, HDAC5 is required for long-term memory formation (2016)](https://pubmed.ncbi.nlm.nih.gov/27618449/)
[Marathe HG, Mehta G, Zhang X, et al, HDAC5 represses the p38 MAPK signaling pathway by targeting MAPK14 (2018)](https://doi.org/10.1128/MCB.00597-17)
[Hu YB, Zou YL, Jia YB, et al, HDAC5: a promising therapeutic target in neurodegenerative diseases (2022)](https://doi.org/10.3389/fnagi.2022.852540)
[Bardai FH, Price V, Zaury L, et al, Diminished activity of HDAC5 in Huntington's disease disease brain contributes to the formation of polyglutamine aggregates (2019)](https://pubmed.ncbi.nlm.nih.gov/30689868/)
[Thomas EA, Coppola G, Desplats PA, et al, The HDAC inhibitor 4b ameliorates the disease phenotype in cellular and mouse models of Huntington disease (2008)](https://doi.org/10.1172/JCI34341)
[Broide RS, Redwine JM, Aftahi N, et al, Distribution of histone deacetylases 1, 2, and 3 in rat brain (2007)](https://pubmed.ncbi.nlm.nih.gov/17167137/)
[Gray SG, Epigenetic therapy in neurodegenerative disease (2023)](https://doi.org/10.1016/j.tig.2023.01.006)
[Consalvi S, Saccone V, Giordani L, Minetti G, Mozzetta C, Puri PL, Histone deacetylase inhibitors in the treatment of muscular dystrophies: epigenetic therapy for Duchenne muscular dystrophy (2023)](https://pubmed.ncbi.nlm.nih.gov/36597983/)
[Mihaylova MM, Shaw RJ, The AMPK signalling pathway coordinates cell growth, autophagy and metabolism (2011)](https://pubmed.ncbi.nlm.nih.gov/21849697/)Pathway Diagram
The following diagram shows the key molecular relationships involving HDAC5 Gene discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)