Histone Deacetylases (HDACs)

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Histone Deacetylases (HDACs)

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Introduction

Histone Deacetylases (Hdacs) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

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Introduction

Histone Deacetylases (Hdacs) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

Mermaid diagram (expand to render)

Histone deacetylases (HDACs) are enzymes that remove acetyl groups from lysine residues on histone proteins["@grff2013"], playing crucial [@dietz2010]
roles in epigenetic regulation of gene expression["@grff2013"][@dietz2010][@grff2013]. Beyond histone modification, HDACs target numerous non-histone proteins involved in neuronal function, [@xu2011]
synaptic plasticity, and neurodegeneration["@dietz2010"]. [@johnson2022]

Classification

Class I HDACs (Zn²⁺-dependent)

HDAC1 (18q22): Primarily nuclear, expressed in most tissues
HDAC2 (6q21): Neuronally enriched, critical for synaptic plasticity[@xu2011]
HDAC3 (5q31): Expressed in brain, associated with transcriptional repression
HDAC8 (Xp11.23): Primarily in smooth muscle and heart

Class IIa HDACs (Zn²⁺-dependent)

HDAC4 (2q37.3): Activity-dependent nuclear-cytoplasmic shuttling[@johnson2022]
HDAC5 (18q11): Neuronal activity-dependent function
HDAC7 (12q13): Expressed in heart and skeletal muscle
HDAC9 (7p15-p14): Expressed in brain and muscle

Class IIb HDACs (Zn²⁺-dependent)

HDAC6 (Xp11.23): Primarily cytoplasmic, deacetylates α-tubulin[@simespires2013]
HDAC10 (22q13): Lysosomal degradation

Class III HDACs (NAD⁺-dependent, Sirtuins)

SIRT1-7: Deacetylases with diverse cellular functions[@consolidation2009]

Class IV HDACs

HDAC11 (3p12): Least characterized

Normal Function in the Brain

Epigenetic Regulation

Repress transcription by deacetylating histones
Dynamic regulation of gene expression programs
Critical for neuronal development and differentiation

Synaptic Plasticity

HDAC2 negatively regulates memory formation[@xu2011]
HDAC2 and HDAC3 modulate synaptic plasticity
Activity-dependent histone acetylation is crucial for [LTP](/mechanisms/long-term-potentiation)

Non-histone Targets

p53, [NF-κB](/entities/nf-kb), STAT3
α-Tubulin (HDAC6)
[Heat shock proteins](/entities/heat-shock-proteins)

Role in Neurodegenerative Diseases

Alzheimer's Disease

HDAC2 is elevated in AD brain and correlates with memory deficits[@sleiman2009]
HDAC6 aggregates in AD brain and affects [tau](/proteins/tau) pathology[@simespires2013]
Class I HDACs promote [Amyloid-Beta](/proteins/amyloid-beta) production[@dietz2010]
[HDAC](/entities/hdac-enzymes) inhibition improves memory in AD models[@langley2014]

Parkinson's Disease

SIRT1 has neuroprotective effects[@consolidation2009]
HDAC inhibitors protect dopaminergic [neurons](/entities/neurons)
[α-Synuclein](/proteins/alpha-synuclein) acetylation affects aggregation

Huntington's Disease

HDAC inhibitors are therapeutic candidates[@jia2019]
Mutant [huntingtin](/proteins/huntingtin-protein) interacts with HDACs
Transcriptional dysregulation involves HDAC function

Amyotrophic Lateral Sclerosis (ALS)

HDAC levels altered in motor neurons
HDAC inhibitors show promise in preclinical models[@chuang2009]

Therapeutic Targeting

HDAC Inhibitors in Clinical Trials

Several HDAC inhibitors are being tested: [@simespires2013]

VPA (Valproic Acid): Class I inhibitor, tested in AD and ALS
SAHA (Vorinostat): Approved for cancer, being repurposed
CI-994: Being investigated for neurodegenerative diseases

Challenges

Lack of brain-penetrant, isoform-selective inhibitors
Side effects from broad HDAC inhibition
Need for better understanding of isoform-specific functions

External Links

[HDAC Classification - Nature](https://www.nature.com/articles/nrm2331)
[HDAC Inhibitors in Neurodegeneration - PMC](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2731018/)
[Sirtuins and Neurodegeneration - Frontiers](https://www.frontiersin.org/articles/10.3389/fncel.2022.983278/full)

Brain Atlas Resources

Allen Human Brain Atlas: [Histone Deacetylases expression search](https://human.brain-map.org/microarray/search/show?search_term=Histone+Deacetylases)
Allen Mouse Brain Atlas: [Histone Deacetylases search](https://mouse.brain-map.org/search/index.html?query=Histone+Deacetylases)
Allen Cell Type Atlas: [Transcriptomic cell type reference](https://portal.brain-map.org/atlases-and-data/rnaseq)
BrainSpan Developmental Transcriptome: [Histone Deacetylases developmental expression](https://www.brainspan.org/rnaseq/search/index.html?search_term=Histone+Deacetylases)

Background

The study of Histone Deacetylases (Hdacs) has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development. [@consolidation2009]

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions. [@sleiman2009]

Additional evidence sources: [@langley2014] [@jia2019] [@chuang2009]

References

Gräff J, Tsai LH, Histone acetylation: molecular mnemonics on chromatin (2013)

Dietz KC, Casaccia P, HDAC inhibitors and neurodegeneration: at the edge between magic bullets and magic poisons (2010)

Xu K, Dai XL, Huang HC, et al, Targeting HDACs: a promising therapy for Alzheimer's Disease (2011)

Johnson AA, Sathigramsiri K, Sheppard HM, et al, The role of HDACs in the response of the brain to metabolic stress (2022)

Simões-Pires C, Zwick V, Nurisso A, et al, HDAC6 as a target for neurodegenerative diseases: what makes it different from classical HDACs? J Alzheimers Dis (2013)

Unknown, consolidation of memory. Nat Rev Neurosci. 2009;10(9):615-620 (2009)

Sleiman SF, Basso M, Mahishi L, et al, Putting the 'kinase' in 'neurodegeneration': is HDAC a reasonable target? Expert Opin Ther Targets (2009)

Langley B, Gensert JM, Therapeutic targeting of REST in Huntington's Disease (2014)

Jia H, Morris CD, Williams RM, et al, HDAC6 inhibitor accelerates pathology and improves memory in a tauopathy mouse model (2019)

Chuang DM, Leng Y, Marinova Z, et al, Multiple roles of HDAC inhibition in neurodegenerative conditions (2009)

Pathway Diagram

The following diagram shows the key molecular relationships involving Histone Deacetylases (HDACs) discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

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📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

55%

Debates

0

Incoming

11

Outgoing

16

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

Histone Deacetylases (HDACs)

Introduction

Overview

Introduction

Overview

Classification

Class I HDACs (Zn²⁺-dependent)

Class IIa HDACs (Zn²⁺-dependent)

Class IIb HDACs (Zn²⁺-dependent)

Class III HDACs (NAD⁺-dependent, Sirtuins)

Class IV HDACs

Normal Function in the Brain

Epigenetic Regulation

Synaptic Plasticity

Non-histone Targets

Role in Neurodegenerative Diseases

Alzheimer's Disease

Parkinson's Disease

Huntington's Disease

Amyotrophic Lateral Sclerosis (ALS)

Therapeutic Targeting

HDAC Inhibitors in Clinical Trials

Challenges

External Links

Brain Atlas Resources

See Also

Background

References

Pathway Diagram

💬 Discussion