KDM1A (Lysine Specific Demethylase 1A)

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KDM1A (Lysine Specific Demethylase 1A)

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">KDM1A</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>KDM1A</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Lysine Specific Demethylase 1A</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>1p36.22</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>23028</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000136867</td>
</tr>
<tr>
<td class="label">OMIM ID</td>
<td>607042</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>O60341</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td>[Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease), Neurodevelopmental Disorders</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>LSD1 family (Flavin-dependent amine oxidase)</td>
</tr>
</table>

KDM1A (Lysine Specific Demethylase 1A)

Introduction

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KDM1A (Lysine Specific Demethylase 1A)

Introduction

KDM1A (also known as LSD1 — Lysine Specific Demethylase 1) is a crucial epigenetic regulator that catalyzes the removal of methyl groups from histone lysine residues. As a flavin-dependent amine oxidase, KDM1A plays essential roles in chromatin remodeling and gene expression regulation throughout the nervous system. [@shih2011] This enzyme is fundamental to neurodevelopment, synaptic plasticity, memory formation, and its dysregulation is strongly implicated in neurodegenerative diseases including [Alzheimer's Disease](/diseases/alzheimers-disease) (AD) and [Parkinson's Disease](/diseases/parkinsons-disease) (PD). [@bartesaghi2019]

Molecular Function

Catalytic Activity

KDM1A is unique among histone demethylases as it belongs to the flavin-dependent amine oxidase family, distinct from the larger Jumonji C (JmjC) domain-containing demethylases. The enzyme catalyzes the oxidative demethylation of:

H3K4me1/2: Primary repressive target — removal activates gene expression
H3K9me1/2: Primary activating target — removal represses gene expression

The catalytic reaction requires flavin adenine dinucleotide (FAD) as a cofactor, which undergoes redox cycling during the demethylation process. The reaction produces formaldehyde as a byproduct. [@kooistra2012]

Protein Complexes

KDM1A functions primarily within multi-protein complexes that dictate its substrate specificity and genomic targeting:

REST/CoREST Complex: KDM1A partners with REST (RE1 Silencing Transcription Factor) and CoREST to repress neuronal genes in non-neuronal cells and regulate synaptic plasticity genes
HDAC1/2 Complexes: Association with histone deacetylases enhances repressive function
Androgen Receptor Complex: In prostate and other tissues, modulates hormone-responsive gene expression
Snail/Smad Complexes: Involved in epithelial-mesenchymal transition and developmental processes

The ability of KDM1A to activate or repress transcription depends on which protein complex it is assembled with and which histone marks it targets. [@stefanelli2018]

Role in Neurodevelopment

Neural Progenitor Cells

During embryonic development, KDM1A is essential for proper neural progenitor cell (NPC) differentiation. Loss of KDM1A function leads to:

Impaired neuronal differentiation
Defects in cortical layering
Altered expression of neurodevelopmental transcription factors

Studies in human neural stem cells have shown that KDM1A modulates the genomic landscape and programming of neural development by regulating key developmental genes. [@tavassoly2021]

Synaptic Plasticity and Memory

KDM1A plays a critical role in synaptic plasticity — the cellular basis of learning and memory:

Regulates expression of immediate-early genes (IEGs) such as c-Fos, Arc, and Egr1
Controls dendritic spine morphology and synaptic connectivity
Essential for long-term memory formation and consolidation

Research using conditional knockout mice demonstrates that LSD1 deficiency in neurons impairs synaptic plasticity and memory formation, confirming its crucial role in cognitive function. [@michaelson2017]

Disease Associations

Alzheimer's Disease

KDM1A is increasingly recognized as a key player in AD pathogenesis:

Amyloid-beta effects: Aβ accumulation alters KDM1A localization and activity, leading to dysregulated gene expression
Tau pathology: KDM1A deficiency promotes tau hyperphosphorylation and aggregation in neuronal models
Epigenetic dysregulation: KDM1A-mediated changes in histone methylation contribute to synaptic gene silencing
Therapeutic potential: LSD1 inhibitors show promise in preclinical AD models by reversing synaptic gene downregulation

Studies have shown that LSD1 deficiency promotes neuronal apoptosis and exacerbates tauopathy in AD models, while pharmacological modulation of KDM1A activity may represent a novel therapeutic approach. [@chen2023][@wang2022]

Parkinson's Disease

In PD, KDM1A is implicated through several mechanisms:

Alpha-synuclein regulation: KDM1A activity affects expression and aggregation of [alpha-synuclein](/proteins/alpha-synuclein)
Dopaminergic neuron survival: KDM1A modulates genes critical for dopamine neuron survival
Mitochondrial function: Epigenetic regulation by KDM1A influences mitochondrial dynamics

Intriguingly, LSD1 inhibitors have been shown to reverse alpha-synuclein-induced neurodegeneration in model systems, suggesting potential therapeutic applications. [@zhang2019]

Neurodevelopmental Disorders

Mutations in KDM1A or its interacting partners (particularly REST) are associated with:

Intellectual disability
Autism spectrum disorders
Epilepsy
Neurodevelopmental delay

REST mutations disrupt KDM1A targeting to neuronal genes, leading to improper gene expression patterns during brain development. [@kontaxi2020]

Expression Pattern

KDM1A is widely expressed throughout the brain with highest levels in:

Hippocampus: Particularly CA1 region — critical for memory processing
Cerebral cortex: Layer 2/3 pyramidal neurons
Cerebellum: Purkinje cells
Striatum: Medium spiny neurons

Expression is activity-dependent, with neuronal stimulation (e.g., seizures, learning paradigms) altering KDM1A nuclear localization and activity. [@huang2019]

Therapeutic Implications

LSD1 Inhibitors

Several KDM1A inhibitors are in development for neurological applications:

Irreversible inhibitors: OG-LSD1, iPdyL (pseudoirreversible)
Reversible inhibitors: GSK2879552, CPI-455
Brain-penetrant options: Being optimized for CNS delivery

Clinical Applications

Targeting KDM1A may benefit:

Cognitive enhancement in age-related decline
Disease modification in AD and PD
Neuroprotection in acute brain injury
Modulation of neuroinflammation via microglial regulation

Recent studies highlight LSD1's role in modulating neuroinflammation through epigenetic regulation of microglial activation, offering another therapeutic avenue. [@yang2022][@song2021]

Interactions and Pathways

Key Protein Interactions

| Partner | Function |
|---------|----------|
| [REST](/genes/rest) | Transcriptional repression of neuronal genes |
| [CoREST](/proteins/rcor1) | Corepressor complex formation |
| [HDAC1](/proteins/hdac1)/[HDAC2](/proteins/hdac2) | Chromatin compaction |
| [BDNF](/proteins/bdnf) | Activity-dependent regulation |
| [MEF2](/proteins/mef2a) | Synaptic plasticity modulation |

Signaling Pathways

cAMP/PKA signaling: Activity-dependent KDM1A phosphorylation
MAPK/ERK pathway: Regulates KDM1A nuclear import
Wnt signaling: Cross-talk with demethylase activity
Notch signaling: Developmental gene regulation

Pathway Diagram

The following diagram shows the key molecular relationships involving kdm1a discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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KDM1A (Lysine Specific Demethylase 1A)

KDM1A (Lysine Specific Demethylase 1A)

KDM1A (Lysine Specific Demethylase 1A)

Introduction

KDM1A (Lysine Specific Demethylase 1A)

KDM1A (Lysine Specific Demethylase 1A)

Introduction

Molecular Function

Catalytic Activity

Protein Complexes

Role in Neurodevelopment

Neural Progenitor Cells

Synaptic Plasticity and Memory

Disease Associations

Alzheimer's Disease

Parkinson's Disease

Neurodevelopmental Disorders

Expression Pattern

Therapeutic Implications

LSD1 Inhibitors

Clinical Applications

Interactions and Pathways

Key Protein Interactions

Signaling Pathways

See Also

Pathway Diagram