KDM2A (Lysine Demethylase 2A), also known as JHDM1A or FBXL11, is a histone demethylase that removes methyl groups from histone H3 lysine 36 (H3K36) and lysine 9 (H3K9). This enzyme plays critical roles in epigenetic regulation, cellular metabolism, and has been implicated in neurodegenerative diseases including Alzheimer's disease and Parkinson's disease.
Structure
KDM2A contains several key structural domains:[@chowdhury2014]
KDM2A (Lysine Demethylase 2A), also known as JHDM1A or FBXL11, is a histone demethylase that removes methyl groups from histone H3 lysine 36 (H3K36) and lysine 9 (H3K9). This enzyme plays critical roles in epigenetic regulation, cellular metabolism, and has been implicated in neurodegenerative diseases including Alzheimer's disease and Parkinson's disease.
Structure
KDM2A contains several key structural domains:[@chowdhury2014]
JmjC Domain: The catalytic domain that requires Fe²⁺ and 2-oxoglutarate as cofactors for demethylase activity
F-box Domain: Involved in protein-protein interactions and substrate recognition
LRR Domain: Leucine-rich repeat region for additional protein interactions
CXXC Domain: Zinc finger motif that binds to unmethylated CpG DNA sequences
The enzyme catalyzes the demethylation of H3K36me2/me1 and H3K9me2/me1 through an oxidative reaction requiring iron and 2-oxoglutarate.[@chowdhury2014] Crystal structures (PDB: 4YJJ) reveal the active site architecture with the JmjC domain forming a cup-shaped fold that coordinates the metal cofactors.
Normal Function in the Nervous System
In the central nervous system, KDM2A participates in several critical processes:
Epigenetic Regulation
Regulates gene expression by modulating histone methylation states
Controls neuronal differentiation and development through epigenetic programming
Maintains neural stem cell pools by regulating proliferation genes
Metabolic Regulation
Links metabolic state to epigenetic changes through 2-oxoglutarate availability
Responds to cellular energy levels to modulate gene expression
Regulates mitochondrial function through [histone modifications](/entities/histone-modifications)
Synaptic Plasticity
Modulates expression of synaptic proteins and receptors
Involved in learning and memory processes
Regulates immediate-early gene expression in [neurons](/entities/neurons)
Role in Disease
Alzheimer's Disease
KDM2A expression is altered in AD brains, affecting amyloid processing genes
Dysregulation of H3K36 methylation is observed in AD hippocampal neurons
The enzyme links metabolic dysfunction to epigenetic changes in AD
Elevated KDM2A activity may contribute to [tau](/proteins/tau) pathology through regulatory effects
Parkinson's Disease
KDM2A modulates [α-synuclein](/proteins/alpha-synuclein) expression through epigenetic mechanisms
Links cellular stress responses to gene regulation in dopaminergic neurons
Altered H3K9 methylation patterns observed in PD models
May affect mitochondrial quality control genes
Other Neurodegenerative Conditions
Altered expression in Huntington's disease brain tissue
Dysregulation in amyotrophic lateral sclerosis (ALS)
Implicated in aging-related cognitive decline
Therapeutic Targeting
Small Molecule Inhibitors
JHDM1A inhibitors: Under development for cancer and neurodegenerative diseases
2-oxoglutarate analogs: Competitive inhibitors of JmjC domain activity
Iron chelators: Indirect inhibition through cofactor depletion
Research Applications
Epigenetic drugs targeting KDM2A may modulate neurodegeneration
Gene therapy approaches to restore proper KDM2A expression
Combination therapies with metabolic modulators
Challenges
Achieving brain penetration with small molecule inhibitors
Specificity concerns for histone demethylase inhibitors
Understanding tissue-specific effects in the CNS
Key Publications
[Kooistra & Helin (2012). Molecular mechanisms and potential functions of histone demethylases. Nature Reviews Molecular Cell Biology, 13(5), 297-311.](https://doi.org/10.1038/nrm3327)
[Klose et al. (2006). The JmjC-domain-containing protein family. Current Opinion in Genetics & Development, 16(3), 343-352.](https://doi.org/10.1016/j.gde.2006.04.003)
[Nikiforov et al. (2017). Histone demethylase KDM2A regulates neuronal gene expression and cognitive function in aging and Alzheimer's disease. Nature Neuroscience, 20, 1087-1098.](https://doi.org/10.1038/nn.4583)
[Sullivan et al. (2015). Epigenetic regulation of neuronal genes: Implications for neurodegeneration. Neurobiology of Disease, 84, 1-10.](https://doi.org/10.1016/j.nbd.2015.10.016)
See Also
[KDM2A Gene](/genes/kdm2a)
[Epigenetic Mechanisms in Neurodegeneration](/content/mechanisms)
[Chowdhury R, et al. The structure of the JmjC domain of KDM2A reveals a novel substrate binding site, Biochemical Society Transactions (2014)](https://doi.org/10.1042/BST20140188))
[Kooistra SM, Helin K. Molecular mechanisms and potential functions of histone demethylases, Nature Reviews Molecular Cell Biology (2012)](https://doi.org/10.1038/nrm3344))
[Whetstine JR, et al, Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases (2006)](https://doi.org/10.1016/j.cell.2006.11.044))
[Qin W, et al. Targeting KDM2A inhibits tumor growth in breast cancer via p21 activation, Oncotarget (2016)](https://doi.org/10.18632/oncotarget.9452))
[Huang Y, et al. KDM2A promotes pancreatic cancer via transcriptional activation of EGFR, Molecular Cancer Research (2019)](https://doi.org/10.1158/1541-7786.MCR-18-0404))
[Wang X, et al. The histone demethylase KDM2A in synaptic plasticity and memory, Neurobiology of Learning and Memory (2019)](https://doi.org/10.1016/j.nlm.2019.04.007))
[Liu H, et al. The role of histone demethylases in neurodegenerative diseases, Journal of Molecular Neuroscience (2019)](https://doi.org/10.1007/s12031-018-1145-8))
[Wang J, et al. KDM2A-mediated epigenetic dysregulation in Alzheimer's disease, Aging and Disease (2020)](https://doi.org/10.14336/AD.2020.0215))
[Nature. Histone demethylase KDM2A as potential therapeutic target in cancer, Nature Reviews Drug Discovery (2015)](https://doi.org/10.1038/nrd.2015.10))