HDAC5 Gene

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HDAC5 Gene

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HDAC5 Gene

Introduction

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HDAC5 Gene

Introduction

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<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 signals

Post-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 transcription

Signal 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 criteria

Interacting 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 proteins

Biomarkers

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

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)

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Related Entities

HDAC5

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slug	genes-hdac5
kg_node_id	HDAC5
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-26fe2db72d71
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-hdac5'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

75%

Debates

0

Incoming

15

Outgoing

23

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

HDAC5 Gene

HDAC5 Gene

Introduction

HDAC5 Gene

Introduction

Gene Overview

Protein Structure

Domain Architecture

Post-translational Modifications

Biological Functions

Epigenetic Regulation

Neuronal Functions

Signal Transduction

Role in Neurodegenerative Diseases

Alzheimer's Disease

Parkinson's Disease

Huntington's Disease

Other Neurodegenerative Disorders

Expression Pattern

Brain Regional Distribution

Development

Therapeutic Target

HDAC Inhibitors

Challenges

Interacting Proteins

Transcription Factors

Co-repressor Complexes

Signaling Proteins

Research Methods

Experimental Approaches

Biomarkers

See Also

External Links

References

Pathway Diagram

💬 Discussion