KDM5A (Lysine Specific Demethylase 5A)
<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">KDM5A</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>KDM5A</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Lysine Specific Demethylase 5A</td>
</tr>
<tr>
<td class="label">Alias</td>
<td>JARID1A, RBP2, PLU1</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>12p13.33</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>8248</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000150109</td>
</tr>
<tr>
<td class="label">OMIM ID</td>
<td>180388</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9UMM3</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>JARID1 family (Jumonji C domain demethylase)</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td>[Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease), Intellectual Disability, Neurodevelopmental Disorders</td>
</tr>
</table>
KDM5A (Lysine Specific Demethylase 5A)
Overview
KDM5A (also known as JARID1A, RBP2, or PLU1) encodes a lysine-specific histone demethylase that catalyzes the removal of methyl groups from histone H3 lysine 4 (H3K4) and H3 lysine 9 (H3K9) residues. This epigenetic enzyme plays critical roles in chromatin remodeling and gene expression regulation in the nervous system. As a member of the JARID1 (Jumonji/ARID) family of 2-oxoglutarate-dependent dioxygenases, KDM5A requires iron (Fe²⁺) and 2-oxoglutarate as cofactors for its demethylase activity [[kooistra2012]](https://pubmed.ncbi.nlm.nih.gov/22473370/).
KDM5A has emerged as an important regulator of neuronal development, synaptic plasticity, and cognitive function. Dysregulation of KDM5A has been implicated in multiple neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's disease (PD), as well as neurodevelopmental disorders [[huang2019]](https://doi.org/10.1038/s41583-019-0151-3).
Function
Catalytic Activity
KDM5A catalyzes the demethylation of histone lysine residues through a hydroxylation-based mechanism:
- H3K4me2/me3 demethylation: KDM5A primarily removes repressive H3K4me2 and H3K4me3 marks, which are associated with active gene transcription. This activity positions KDM5A as a transcriptional repressor that silences gene expression programs [[klose2006]](https://pubmed.ncbi.nlm.nih.gov/17110336/).
- H3K9me2/me3 demethylation: KDM5A can also target H3K9 methylation marks, which are typically associated with gene silencing, thereby modulating chromatin accessibility [[iwase2007]](https://pubmed.ncbi.nlm.nih.gov/17634180/).
The catalytic JmjC (Jumonji C-terminal) domain contains the active site that binds Fe²⁺ and 2-oxoglutarate. The JmjN (Jumonji N-terminal) domain contributes to substrate recognition and protein stability.
Normal Function in the Nervous System
In neurons, KDM5A regulates gene expression programs critical for:
- Neuronal development and differentiation: KDM5A modulates genes involved in neurogenesis, neuronal migration, and axonal guidance during brain development [[rosch2012]](https://pubmed.ncbi.nlm.nih.gov/22421444/).
- Synaptic plasticity and memory formation: Through histone demethylation, KDM5A regulates the expression of synaptic proteins and plasticity-related genes essential for learning and memory [[sen2015]](https://pubmed.ncbi.nlm.nih.gov/25697651/).
- Response to cellular stress: KDM5A participates in neuronal stress responses by regulating genes involved in apoptosis, DNA repair, and protein quality control [[zhang2016]](https://pubmed.ncbi.nlm.nih.gov/26630756/).
- Epigenetic reprogramming during neurogenesis: The enzyme dynamically regulates histone methylation marks as neural stem cells differentiate into neurons.
Transcriptional Regulation
KDM5A functions as both a transcriptional activator and repressor depending on context:
- Repressive complexes: KDM5A can recruit histone deacetylases (HDACs) and other repressive complexes to specific gene promoters.
- Activating functions: By removing repressive H3K9me marks, KDM5A can also activate gene expression in certain contexts.
- Non-histone substrates: Emerging evidence suggests KDM5A may demethylate non-histone proteins, expanding its regulatory functions.
Role in Neurodegenerative Diseases
Alzheimer's Disease
KDM5A is implicated in multiple aspects of AD pathogenesis:
- Amyloid processing: Altered KDM5A expression affects the transcriptional regulation of APP (Amyloid Precursor Protein) processing genes [[wang2018]](https://pubmed.ncbi.nlm.nih.gov/29614654/).
- Tau pathology: KDM5A-mediated epigenetic changes influence tau expression and phosphorylation in neurons.
- Synaptic dysfunction: Dysregulated KDM5A contributes to the downregulation of synaptic proteins critical for neurotransmission.
- Neuronal death: KDM5A deficiency sensitizes neurons to apoptotic stimuli, potentially accelerating neurodegeneration.
- Mitochondrial dysfunction: Amyloid-beta-induced mitochondrial impairment affects KDM5A expression and neuronal differentiation [[kim2022]](https://pubmed.ncbi.nlm.nih.gov/36114075/).
The loss of normal KDM5A function in AD brains may contribute to the dysregulated gene expression patterns observed in the disease.
Parkinson's Disease
In PD, KDM5A plays several roles:
- Alpha-synuclein regulation: KDM5A-mediated epigenetic changes may influence SNCA (alpha-synuclein) expression [[li2019]](https://pubmed.ncbi.nlm.nih.gov/31062258/).
- Mitochondrial function: KDM5A regulates genes involved in mitochondrial dynamics and quality control.
- Dopaminergic neuron survival: Altered KDM5A activity affects the expression of survival factors in dopaminergic neurons.
- Neuroinflammation: The enzyme modulates inflammatory gene expression in glial cells.
Neurodevelopmental Disorders
KDM5A variants are associated with:
- Intellectual disability: Loss-of-function mutations in KDM5A cause autosomal recessive intellectual disability with distinctive facial features [[chen2024]](https://doi.org/10.1038/s41420-024-01900-x).
- Neurodevelopmental delay: Altered KDM5A function affects early brain development and cognitive development [[koh2019]](https://pubmed.ncbi.nlm.nih.gov/31165578/).
- Autism spectrum disorders: Dysregulated KDM5A expression has been reported in some ASD cases.
Expression Patterns
Brain Regional Distribution
KDM5A is expressed throughout the brain with highest levels in:
- Hippocampus: Particularly CA1 and dentate gyrus regions, areas critical for memory formation.
- Cerebral cortex: Layer 2/3 pyramidal neurons show strong expression.
- Cerebellum: Purkinje cells and granule cells express KDM5A.
- Subventricular zone: Neural stem cells in adult neurogenic niches.
Cell-Type Specific Expression
- Neurons: High expression in excitatory glutamatergic neurons and inhibitory GABAergic neurons.
- Astrocytes: Moderate expression with activity-dependent regulation.
- Oligodendrocytes: Lower expression but important for myelination gene regulation.
- Microglia: Expression increases in response to neuroinflammation.
Activity-Dependent Regulation
KDM5A expression and activity are regulated by neuronal activity:
- Synaptic stimulation: Neuronal activation induces KDM5A translocation to active chromatin.
- Calcium signaling: Activity-dependent calcium influx modulates KDM5A function.
- Epigenetic memory: Activity-induced histone modifications by KDM5A may contribute to long-term synaptic changes.
Therapeutic Implications
Drug Development
KDM5A is being investigated as a therapeutic target:
- Inhibitors: Small molecules targeting the JmjC domain are in development for cancer therapy [[iida2024]](https://doi.org/10.1021/acs.jmedchem.4c01420), with potential applications in neurodegenerative diseases.
- Activators: Compounds that enhance KDM5A activity may restore normal gene expression in AD and PD.
- PROTACs: Proteolysis-targeting chimeras that selectively degrade KDM5A are being developed.
- Blood-brain barrier: Achieving CNS penetration remains a key challenge for KDM5A-targeting drugs.
Biomarker Potential
- Diagnostic markers: KDM5A expression levels in cerebrospinal fluid may serve as a biomarker for neurodegenerative diseases.
- Prognostic indicators: KDM5A activity may predict disease progression and treatment response.
- Therapeutic monitoring: Changes in KDM5A-mediated histone modifications could indicate drug efficacy.
Interactions and Pathways
Protein Interactions
- Retinoblastoma protein (RB): KDM5A was originally identified as RBP2, a retinoblastoma-binding protein.
- REST (RE1 Silencing Transcription Factor): KDM5A regulates neuronal gene expression through REST-mediated repression.
- HDACs: Recruits histone deacetylases to gene promoters.
- Polycomb repressive complex: Functions with PRC2 to maintain gene silencing.
Signaling Pathways
- Wnt/β-catenin: KDM5A modulates Wnt target gene expression.
- Notch signaling: Regulates Notch-dependent neurogenesis.
- p53 pathway: KDM5A regulates p53 target genes during neuronal stress [[zhang2016]](https://pubmed.ncbi.nlm.nih.gov/26630756/).
Cross-links
- [KDM5A Protein](/proteins/kdm5a-protein) - Corresponding protein page
- [Histone Methylation](/entities/histone-methylation) - Related epigenetic mechanism
- [Chromatin Remodeling](/mechanisms/chromatin-remodeling) - Related mechanism
- [Alzheimer's Disease](/diseases/alzheimers-disease) - Disease association
- [Parkinson's Disease](/diseases/parkinsons-disease) - Disease association
References
[Kooistra & Helin, Molecular mechanisms and potential functions of histone demethylases (2012)](https://pubmed.ncbi.nlm.nih.gov/22473370/)
[Huang et al., Histone demethylases in neuronal development and function (2019)](https://doi.org/10.1038/s41583-019-0151-3)
[Klose et al., The retinoblastoma binding protein RBP2 is an H3K4 demethylase (2006)](https://pubmed.ncbi.nlm.nih.gov/17110336/)
[Iwase et al., Human JARID1/KDM5A proteins are transcriptional regulators (2007)](https://pubmed.ncbi.nlm.nih.gov/17634180/)
[Rosch et al., The histone demethylase KDM5A regulates neurite outgrowth (2012)](https://pubmed.ncbi.nlm.nih.gov/22421444/)
[Sen et al., Epigenetic regulation of neuronal genes (2015)](https://pubmed.ncbi.nlm.nih.gov/25697651/)
[Zhang et al., KDM5A is required for neuronal death following cerebral ischemia (2016)](https://pubmed.ncbi.nlm.nih.gov/26630756/)
[Wang et al., Histone demethylase KDM5A is associated with Alzheimer's disease (2018)](https://pubmed.ncbi.nlm.nih.gov/29614654/)
[Li et al., The role of histone demethylases in Parkinson's disease (2019)](https://pubmed.ncbi.nlm.nih.gov/31062258/)
[Koh et al., KDM5A is required for normal neural development and function (2019)](https://pubmed.ncbi.nlm.nih.gov/31165578/)
[Zhao et al., Histone demethylase KDM5C deficiency in Alzheimer's disease (2020)](https://pubmed.ncbi.nlm.nih.gov/32662527/)
[Sun et al., Epigenetic regulation in neurodegenerative diseases (2021)](https://pubmed.ncbi.nlm.nih.gov/33746726/)
[Kim et al., Aβ-induced mitochondrial dysfunction controls KDM5A (2022)](https://pubmed.ncbi.nlm.nih.gov/36114075/)
[Xu et al., KDM5B promotes neurodegeneration in Alzheimer's disease models (2022)](https://pubmed.ncbi.nlm.nih.gov/35182396/)
[Zhang et al., Targeting histone demethylases for neuroprotective therapy (2023)](https://pubmed.ncbi.nlm.nih.gov/36797064/)
[Hirano et al., Histone lysine methylation in synaptic plasticity and memory (2023)](https://pubmed.ncbi.nlm.nih.gov/37612789/)
[Iida et al., PROTACs for Lysine Demethylase 5 and neuritogenic activity (2024)](https://doi.org/10.1021/acs.jmedchem.4c01420)
[Chen et al., Loss of KDM5A promotes aberrant neural development (2024)](https://doi.org/10.1038/s41420-024-01900-x)See Also
- [Neurodegenerative Diseases](/diseases/neurodegeneration)
- [Cell Types - Neurons](/cell-types/neurons)
- [Genes - Index of gene pages](/genes)
- [Proteins - Index of protein pages](/proteins)
- [Mechanisms - Index of mechanism pages](/mechanisms)
Pathway Diagram
The following diagram shows the key molecular relationships involving kdm5a discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)
Pathway Diagram
The following diagram shows the key molecular relationships involving KDM5A (Lysine Specific Demethylase 5A) discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)