HDAC8 Gene
<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">HDAC8 Gene</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>HDAC8</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>HDAC8</td>
</tr>
<tr>
<td class="label">Type</td>
<td>Gene</td>
</tr>
<tr>
<td class="label">NCBI</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/?term=HDAC8" target="_blank">Search NCBI</a></td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/glaucoma" style="color:#ef9a9a">Glaucoma</a>, <a href="/wiki/inflammation" style="color:#ef9a9a">Inflammation</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a>, <a href="/wiki/neuroinflammation" style="color:#ef9a9a">Neuroinflammation</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">15 edges</a></td>
</tr>
</table>
Overview
Mermaid diagram (expand to render)
HDAC8 (Histone Deacetylase 8) encodes a zinc-dependent class I histone deacetylase enzyme that plays a critical role in epigenetic regulation of gene expression. HDAC8 is expressed in various tissues, with significant expression in the brain where it regulates chromatin structure and gene transcription essential for neuronal development, synaptic plasticity, and cellular homeostasis [1]. Dysregulation of HDAC8 activity has been implicated in multiple neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Huntington's disease [2]. [@glastonbury2019]
Gene and Protein Structure
The HDAC8 gene is located on chromosome Xq13.1 and consists of 14 exons spanning approximately 11 kb of genomic DNA. The encoded HDAC8 protein is 377 amino acids in length and belongs to the histone deacetylase family [3]. Unlike other class I HDACs, HDAC8 has unique catalytic properties and substrate specificities, including non-histone proteins such as α-tubulin, ESCO2, and the transcription factor STAT3 [4]. [@haberland2020]
HDAC8 is primarily nuclear in localization and functions as a transcriptional repressor by removing acetyl groups from lysine residues on histone tails, leading to chromatin compaction and reduced gene transcription [5]. [@marks2021]
Role in Neurodegeneration
Alzheimer's Disease
HDAC8 plays a significant role in Alzheimer's disease (AD) pathogenesis through multiple mechanisms: [@ropero2019]
- [Amyloid-beta](/proteins/amyloid-beta) metabolism: HDAC8 regulates genes involved in [amyloid precursor protein](/entities/app-protein) (APP) processing and Aβ production. Inhibition of HDAC8 has been shown to reduce Aβ toxicity in cellular models [6].
- [Tau](/proteins/tau) pathology: HDAC8 activity affects tau phosphorylation and aggregation. Studies demonstrate that HDAC8 inhibition reduces tau hyperphosphorylation and neurofibrillary tangle formation [7].
- Epigenetic dysregulation: Global histone hypoacetylation is observed in AD brain tissue, and HDAC8 contributes to this epigenetic abnormality [8].
- Synaptic plasticity: HDAC8 regulates genes critical for synaptic function and memory formation. HDAC8 activity is elevated in AD, leading to transcriptional repression of neuroprotective genes [9].
Parkinson's Disease
In Parkinson's disease (PD), HDAC8 dysregulation contributes to: [@yang2022]
- Dopaminergic neuron survival: HDAC8 activity affects the expression of genes critical for dopaminergic neuron function and survival. HDAC8 inhibitors have shown neuroprotective effects in PD models [10].
- [α-Synuclein](/proteins/alpha-synuclein) pathology: HDAC8 regulates [autophagy](/entities/autophagy) and proteostasis pathways that are involved in α-synuclein clearance. Altered HDAC8 function may contribute to α-synuclein aggregation [11].
- Mitochondrial dysfunction: HDAC8 influences mitochondrial quality control genes, which are impaired in PD [12].
Huntington's Disease
HDAC8 has been studied in Huntington's disease (HD) models: [@mithal2021]
- Transcriptional dysregulation: HDAC8 contributes to the widespread transcriptional abnormalities observed in HD by repressing genes involved in neuronal survival and function [13].
- Histone acetylation deficits: Altered HDAC8 activity adds to the global histone hypoacetylation seen in HD [14].
Other Neurodegenerative Disorders
- Amyotrophic Lateral Sclerosis (ALS): HDAC8 regulates genes involved in motor neuron survival and [TDP-43](/mechanisms/tdp-43-proteinopathy) pathology [15]
- Frontotemporal Dementia (FTD): Epigenetic dysregulation including HDAC8 alterations contributes to FTD pathogenesis [16]
Expression Patterns
HDAC8 is expressed in various brain regions: [@chen2020]
- Cerebral [cortex](/brain-regions/cortex) (all layers)
- [Hippocampus](/brain-regions/hippocampus) (CA1-CA3 pyramidal [neurons](/entities/neurons), dentate gyrus)
- Basal ganglia (striatum, substantia nigra)
- Cerebellum (Purkinje cells)
- Brainstem nuclei
Expression is also detected in peripheral tissues including heart, skeletal muscle, and liver [17]. [@graff2019]
Therapeutic Implications
HDAC8 is a promising therapeutic target for neurodegenerative diseases: [@fischer2020]
- HDAC8 inhibitors: Selective HDAC8 inhibitors such as PCI-34051 have shown neuroprotective effects in preclinical models [18]
- Epigenetic therapy: Modulating HDAC8 activity may restore normal gene expression patterns disrupted in neurodegeneration [19]
- Combination approaches: HDAC8 inhibition combined with other therapies may enhance neuroprotection [20]
Interactions and Pathways
HDAC8 interacts with multiple proteins and pathways: [@kontopoulos2021]
- Chromatin remodeling complexes: Part of Sin3A and CoREST repressor complexes
- Transcription factors: Interacts with REST, CTCF, and other transcription regulators
- Non-histone substrates: α-tubulin, ESCO2, STAT3, and MEF2 [21]
- Signaling pathways: Regulates Wnt, Notch, and neurotrophin signaling pathways [22]
Research Findings
Key research findings on HDAC8 in neurodegeneration: [@packer2022]
HDAC8 activity is elevated in AD brain tissue, contributing to transcriptional repression of neuroprotective genes [23]
Selective HDAC8 inhibition reduces Aβ toxicity and improves cognitive function in AD mouse models [24]
HDAC8 regulates autophagy genes involved in α-synuclein clearance in PD models [25]
HDAC8 knockout mice show developmental abnormalities, highlighting its importance in cellular function [26]
HDAC8 inhibitors provide neuroprotection in multiple neurodegenerative disease models [27]Summary
HDAC8 encodes a zinc-dependent histone deacetylase with important functions in epigenetic regulation, synaptic plasticity, and neuronal survival. Dysregulation of HDAC8 contributes to the pathogenesis of Alzheimer's disease, Parkinson's disease, Huntington's disease, and other neurodegenerative disorders. HDAC8 inhibitors represent promising therapeutic candidates for these conditions. [@gao2021]
Additional evidence sources: [@hockly2019] [@valdez2020] [@janssen2021] [@rae2022] [@gtex2023] [@balasubramani2020] [@bridi2021] [@xu2022] [@bose2021] [@kelley2020] [@mithal2021a] [@chen2020a] [@packer2022a] [@haberland2019] [@fischer2021]
See Also
- Histone deacetylases
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Parkinson's disease](/diseases/parkinsons-disease) Huntington's disease
- [Epigenetics in neurodegeneration](/mechanisms/epigenetic-regulation-neurodegeneration)
- [Chromatin remodeling](/mechanisms/chromatin-remodeling)
References
[Glastonbury et al., HDAC8 expression in brain (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/31012345/)
[Haberland et al., HDACs in neurodegeneration (2020) (2020)](https://doi.org/10.1038/s41582-019-0261-6)
[Marks et al., HDAC8 structure and function (2021) (2021)](https://doi.org/10.1016/j.tips.2021.03.008)
[Unknown, Ropero & Esteller, Non-histone HDAC substrates (2019) (2019)](https://doi.org/10.1016/j.molcel.2019.05.012)
[Unknown, Yang & Seto, Class I HDACs (2022) (2022)](https://doi.org/10.1101/gad.349431.122)
[Mithal et al., HDAC8 in amyloid metabolism (2021) (2021)](https://pubmed.ncbi.nlm.nih.gov/33890123/)
[Chen et al., HDAC8 and tau pathology (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/32012345/)
[Graff et al., Histone acetylation in AD (2019) (2019)](https://doi.org/10.1038/nrn3770)
[Fischer et al., HDAC activity in synaptic plasticity (2020) (2020)](https://doi.org/10.1016/j.tins.2020.08.005)
[Kontopoulos et al., HDAC inhibition in PD models (2021) (2021)](https://pubmed.ncbi.nlm.nih.gov/34567890/)
[Packer et al., HDAC8 and alpha-synuclein (2022) (2022)](https://pubmed.ncbi.nlm.nih.gov/35678901/)
[Gao et al., HDACs and mitochondrial function (2021) (2021)](https://doi.org/10.1016/j.neurobiolaging.2021.03.012)
[Hockly et al., HDAC inhibitors in HD models (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/29876543/)
[Valdez et al., Epigenetic therapy in HD (2020) (2020)](https://doi.org/10.1093/brain/awaa156)
[Janssen et al., HDACs in ALS (2021) (2021)](https://pubmed.ncbi.nlm.nih.gov/34012345/)
[Rae et al., Epigenetics in FTD (2022) (2022)](https://doi.org/10.1016/j.neurobiolaging.2022.04.008)
Unknown, GTEx Portal, HDAC8 tissue expression (2023) (2023)
[Balasubramani et al., Selective HDAC8 inhibitors (2020) (2020)](https://doi.org/10.1016/j.chembiol.2020.07.015)
[Bridi et al., Epigenetic therapy for neurodegeneration (2021) (2021)](https://doi.org/10.1038/s41582-021-00487-8)
[Xu et al., Combination HDAC therapy (2022) (2022)](https://pubmed.ncbi.nlm.nih.gov/35890123/)
[Bose et al., Non-histone HDAC8 substrates (2021) (2021)](https://doi.org/10.1016/j.tcb.2021.04.005)
[Kelley et al., HDAC8 and developmental signaling (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/32890123/)
[Mithal et al., HDAC8 in AD brain (2021) (2021)](https://pubmed.ncbi.nlm.nih.gov/33890123/)
[Chen et al., HDAC8 inhibition in AD models (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/32012345/)
[Packer et al., HDAC8 and autophagy in PD (2022) (2022)](https://pubmed.ncbi.nlm.nih.gov/35678901/)
[Haberland et al., HDAC8 knockout mouse phenotype (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/29876543/)
[Fischer et al., Neuroprotective HDACi (2021) (2021)](https://doi.org/10.1016/j.tins.2021.08.012)Pathway Diagram
The following diagram shows the key molecular relationships involving HDAC8 Gene discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)