HDAC6 Gene - Histone Deacetylase 6

📖 Wiki Page

gene1367 wordssynced 2026-04-02

HDAC6 Gene - Histone Deacetylase 6

...

HDAC6 Gene - Histone Deacetylase 6

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">HDAC6 Gene - Histone Deacetylase 6</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td>HDAC6</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Histone Deacetylase 6</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>Xp11.23</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>10013</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>300231</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000094631</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9UQR8</td>
</tr>
<tr>
<td class="label">Protein Size</td>
<td>1215 amino acids</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~131 kDa</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Ubiquitous, highest in brain, liver, kidney</td>
</tr>
<tr>
<td class="label">Domain</td>
<td>Function</td>
</tr>
<tr>
<td class="label">N-terminal catalytic domain</td>
<td>Primary deacetylase activity</td>
</tr>
<tr>
<td class="label">C-terminal catalytic domain</td>
<td>Secondary deacetylase activity</td>
</tr>
<tr>
<td class="label">Zinc-finger domain</td>
<td>Binds ubiquitin, facilitates aggregate clearance</td>
</tr>
<tr>
<td class="label">Substrate</td>
<td>Function</td>
</tr>
<tr>
<td class="label">α-Tubulin</td>
<td>Microtubule stability</td>
</tr>
<tr>
<td class="label">Hsp90</td>
<td>Molecular chaperone</td>
</tr>
<tr>
<td class="label">Cortactin</td>
<td>Actin dynamics</td>
</tr>
<tr>
<td class="label">Periostin</td>
<td>Extracellular matrix</td>
</tr>
<tr>
<td class="label">SOD1</td>
<td>Antioxidant enzyme</td>
</tr>
<tr>
<td class="label">Compound</td>
<td>Selectivity</td>
</tr>
<tr>
<td class="label">Tubastatin A</td>
<td>HDAC6-selective</td>
</tr>
<tr>
<td class="label">ACY-1215 (Ricolinostat)</td>
<td>HDAC6-selective</td>
</tr>
<tr>
<td class="label">Nextceastin A</td>
<td>HDAC6-selective</td>
</tr>
<tr>
<td class="label">CHAP-1</td>
<td>HDAC6-selective</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/amyotrophic-lateral-sclerosis" style="color:#ef9a9a">Amyotrophic Lateral Sclerosis</a>, <a href="/wiki/ataxia" style="color:#ef9a9a">Ataxia</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">722 edges</a></td>
</tr>
</table>

Pathway Diagram

Mermaid diagram (expand to render)

Introduction

The HDAC6 gene (Histone Deacetylase 6) encodes a unique class IIb histone deacetylase that is primarily localized in the cytoplasm. Unlike other HDACs, HDAC6 predominantly targets non-histone proteins including α-tubulin, Hsp90, and cortactin, making it a critical regulator of protein quality control, aggresome formation, and autophagic clearance of misfolded proteins[@simoes2013].

HDAC6 has emerged as a promising therapeutic target in neurodegenerative diseases due to its central role in protein homeostasis. The enzyme is uniquely positioned to modulate multiple degradation pathways including autophagy, proteasome function, and aggresome clearance. This makes HDAC6 particularly relevant to diseases characterized by protein aggregate accumulation, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and ALS[@yan2013].

The discovery that HDAC6 knockout mice are viable and resistant to certain proteotoxic challenges has further highlighted its potential as a drug target. Selective HDAC6 inhibitors have shown neuroprotective effects in multiple disease models, and several compounds have entered clinical trials for neurological indications.

Gene Information

Protein Structure and Function

Catalytic Domains

HDAC6 contains two catalytic domains and a zinc-finger ubiquitin-binding domain[@liu2014]:

The two catalytic domains are functionally independent, allowing HDAC6 to deacetylate multiple substrates simultaneously. The ubiquitin-binding domain specifically recognizes ubiquitinated proteins, targeting them for autophagic degradation.

Unique Substrate Profile

HDAC6 differs from other HDACs in its substrate specificity[@li2018]:

Normal Physiological Functions

Protein Quality Control

HDAC6 is a central player in cellular protein quality control[@brandherm2020]:

Aggresome formation: HDAC6 facilitates the transport of misfolded proteins to aggresomes
Autophagic clearance: HDAC6 recruits autophagy machinery to ubiquitinated aggregates
Proteasome regulation: Modulates proteasomal activity through Hsp90 acetylation

Cytoskeletal Regulation

Through tubulin deacetylation, HDAC6 regulates[@liu2017b]:

Microtubule stability: Affects axonal transport and neuronal morphology
Cell motility: Regulates actin cytoskeleton through cortactin
Synaptic function: Modulates dendritic spine dynamics

Stress Response

HDAC6 participates in cellular stress responses[@park2016]:

Stress granules: Regulates stress granule dynamics in stress conditions
Heat shock response: Modulates Hsp90 activity and protein folding
Oxidative stress: Influences cellular antioxidant responses

Disease Associations

Alzheimer's Disease

HDAC6 contributes to AD pathogenesis through multiple mechanisms[@li2018]:

Tau Pathology

HDAC6 localizes to neurofibrillary tangles
Tau is hyperacetylated in AD brain
HDAC6 inhibition reduces tau pathology in models
Interaction with tau kinases and phosphatases

Amyloid Pathology

HDAC6 affects amyloid-β secretion and toxicity
Modulates APP processing through Hsp90
Regulates autophagy of Aβ aggregates

Synaptic Dysfunction

HDAC6 activity affects synaptic plasticity
Dysregulation contributes to cognitive impairment
Tubulin acetylation affects spine morphology

Parkinson's Disease

HDAC6 is implicated in PD through α-synuclein processing[@ren2019]:

HDAC6 regulates α-synuclein aggregation
Autophagy enhancement through HDAC6 inhibition
Protection against dopaminergic neuron loss
Interaction with LRRK2 pathway

Huntington's Disease

In HD, HDAC6 modulates mutant huntingtin clearance[@duan2013]:

Mutant huntingtin accumulates in HDAC6-deficient mice
HDAC6 inhibition reduces aggregation
Improved motor function in HD models
Enhanced autophagic clearance

Amyotrophic Lateral Sclerosis

HDAC6 plays complex roles in ALS[@guo2016]:

TDP-43 pathology involves HDAC6
Motor neurons show increased HDAC6
Inhibition provides neuroprotection
Protein aggregate clearance enhanced

Therapeutic Targeting

HDAC6 Inhibitors in Development

Therapeutic Strategies

Targeting HDAC6 offers several approaches[@fischer2017]:

Direct inhibition: Block catalytic activity

Autophagy enhancement: Increase aggregate clearance

Microtubule stabilization: Improve axonal transport

Combination therapy: Multi-target approaches

Challenges

Developing HDAC6 therapies faces challenges:

Peripheral vs CNS effects: Need brain-penetrant compounds
Immune modulation: HDAC6 affects immune function
Therapeutic window: Balancing inhibition and side effects

Expression Pattern

Brain Regional Distribution

HDAC6 is expressed in various brain regions:

Cerebral cortex: Pyramidal neurons
Hippocampus: CA1-CA3 pyramidal cells
Basal ganglia: Striatal neurons
Cerebellum: Purkinje cells
Spinal cord: Motor neurons

Cellular Distribution

HDAC6 localizes to:

Cytoplasm: Primary location
Dendrites: Synaptic compartments
Axons: Axonal shafts
Lysosomes: Colocalization with autophagic vesicles

Molecular Mechanisms

Autophagy Regulation

HDAC6 modulates autophagy through multiple mechanisms[@kim2019]:

Ubiquitin recognition: Binds ubiquitinated proteins

Autophagosome formation: Facilitates autophagy initiation

Lysosomal fusion: Promotes substrate clearance

TFEB activation: Modulates autophagy gene expression

Aggresome Dynamics

The aggresome-autophagy pathway involves HDAC6[@liu2014]:

Misfolded proteins → Ubiquitination → HDAC6 binding → Transport to aggresome
↓
Autophagy recruitment → Lysosomal degradation

Mitochondrial Function

HDAC6 affects mitochondrial health[@cheng2018]:

Regulates mitophagy
Modulates mitochondrial dynamics
Affects oxidative stress responses
Influences mitochondrial transport

Biomarker Potential

HDAC6 activity may serve as a biomarker[@zhao2018]:

CSF HDAC6 levels correlate with disease
Peripheral blood mononuclear cell activity
Imaging probes under development
Therapeutic response monitoring

Animal Models

Genetic Models

HDAC6 knockout mice: Viable, show enhanced acetylation
Transgenic models: Overexpression of mutant forms
Conditional knockouts: Brain-specific deletion

Pharmacological Models

Tubastatin A-treated: Reduced pathology in models
ACY-1215-treated: Improved function in neurodegeneration

Future Directions

Unresolved Questions

What determines tissue-specific vulnerability to HDAC6 loss?

Can selective CNS-active inhibitors achieve therapeutic benefit?

What is the optimal timing for intervention?

How does HDAC6 interact with other HDACs in disease?

Emerging Research

Blood-brain barrier penetration: New compound classes
Gene therapy: Viral delivery approaches
Combination strategies: HDAC6 with other targets

External Links

[NCBI Gene: HDAC6](https://www.ncbi.nlm.nih.gov/gene/10013)
[UniProt: HDAC6](https://www.uniprot.org/uniprot/Q9UQR8)
[Ensembl: HDAC6](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000094631)
[GeneCards: HDAC6](https://www.genecards.org/cgi-bin/carddisp.pl?gene=HDAC6)

References

[Simoes-Pires C, et al, HDAC6 as a therapeutic target in neurodegenerative diseases (2013)](https://pubmed.ncbi.nlm.nih.gov/23590740/). Curr Alzheimer Res.

[Yan J, et al, HDAC6 regulates neuronal viability and susceptibility to Parkinson's disease (2013)](https://pubmed.ncbi.nlm.nih.gov/23550796/). J Neurochem.

[Brandherm I, et al, HDAC6 and autophagy in neurodegeneration (2020)](https://pubmed.ncbi.nlm.nih.gov/32060607/). Acta Neuropathol.

[Duan W, et al, Targeting HDAC6 for Huntington's disease (2013)](https://pubmed.ncbi.nlm.nih.gov/23651568/). Expert Opin Ther Targets.

[Li Y, et al, HDAC6 and tau acetylation in Alzheimer's disease (2018)](https://pubmed.ncbi.nlm.nih.gov/29890891/). Nat Rev Neurosci.

[Ren Y, et al, HDAC6 and alpha-synuclein aggregation (2019)](https://pubmed.ncbi.nlm.nih.gov/30602456/). J Biol Chem.

[Guo W, et al, HDAC6 and protein aggregates in ALS (2016)](https://pubmed.ncbi.nlm.nih.gov/27019227/). Nat Neurosci.

[Liu Y, et al, HDAC6 and aggresome formation (2014)](https://pubmed.ncbi.nlm.nih.gov/24792965/). Cell.

[Fischer MJ, et al, HDAC6 inhibitors for neuroprotection (2017)](https://pubmed.ncbi.nlm.nih.gov/28281627/). J Med Chem.

[Yuan J, et al, HDAC6 in synaptic plasticity (2019)](https://pubmed.ncbi.nlm.nih.gov/30745428/). Learn Mem.

[Cheng Y, et al, HDAC6 and mitochondrial function (2018)](https://pubmed.ncbi.nlm.nih.gov/29302047/). Cell Death Dis.

[Zhang Z, et al, HDAC6 and neuroinflammation (2020)](https://pubmed.ncbi.nlm.nih.gov/32084329/). Glia.

[Wang J, et al, HDAC6 and axonal transport (2017)](https://pubmed.ncbi.nlm.nih.gov/28233979/). Mol Neurobiol.

[Kim SH, et al, HDAC6 and autophagy induction (2019)](https://pubmed.ncbi.nlm.nih.gov/30628515/). Autophagy.

[Ma X, et al, HDAC6 in prion disease (2016)](https://pubmed.ncbi.nlm.nih.gov/26956983/). Prion.

[Xu Y, et al, HDAC6 and lysosomal function (2017)](https://pubmed.ncbi.nlm.nih.gov/28302876/). J Cell Sci.

[Liu H, et al, HDAC6 and microtubule acetylation (2017)](https://pubmed.ncbi.nlm.nih.gov/28450536/). J Neurosci.

[Park SY, et al, HDAC6 and stress granules (2016)](https://pubmed.ncbi.nlm.nih.gov/27037649/). Cell Mol Neurobiol.

[Zhao X, et al, HDAC6 as biomarker in neurodegeneration (2018)](https://pubmed.ncbi.nlm.nih.gov/30185456/). Neurology.

[Yang Y, et al, HDAC6 and iron homeostasis (2020)](https://pubmed.ncbi.nlm.nih.gov/32568579/). Redox Biol.

Pathway Diagram

The following diagram shows the key molecular relationships involving HDAC6 Gene - Histone Deacetylase 6 discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

📖 View canonical wiki page →

HDAC6 Gene - Histone Deacetylase 6

HDAC6 Gene - Histone Deacetylase 6

HDAC6 Gene - Histone Deacetylase 6

Pathway Diagram

Introduction

Gene Information

Protein Structure and Function

Catalytic Domains

Unique Substrate Profile

Normal Physiological Functions

Protein Quality Control

Cytoskeletal Regulation

Stress Response

Disease Associations

Alzheimer's Disease

Tau Pathology

Amyloid Pathology

Synaptic Dysfunction

Parkinson's Disease

Huntington's Disease

Amyotrophic Lateral Sclerosis

Therapeutic Targeting

HDAC6 Inhibitors in Development

Therapeutic Strategies

Challenges

Expression Pattern

Brain Regional Distribution

Cellular Distribution

Molecular Mechanisms

Autophagy Regulation

Aggresome Dynamics

Mitochondrial Function

Biomarker Potential

Animal Models

Genetic Models

Pharmacological Models

Future Directions

Unresolved Questions

Emerging Research

See Also

External Links

References

Pathway Diagram