ATP10B — ATPase Phospholipid Transporting 10B

ATP10B — ATPase Phospholipid Transporting 10B

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">ATP10B — ATPase Phospholipid Transporting 10B</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>ATP10B</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>ATPase Phospholipid Transporting 10B</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>12q24.31</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/23195" target="_blank">23195</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000137727" target="_blank">ENSG00000137727</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/620226" target="_blank">620226</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q9Y5K5" target="_blank">Q9Y5K5</a></td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Parkinson's Disease](/diseases/parkinsons-disease), [Dementia with Lewy Bodies](/diseases/dementia-with-lewy-bodies)</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Substantia Nigra, Brain</td>
</tr>
<tr>
<th class="infobox-subheader" colspan="2">Key Mutations</th>
</tr>
<tr>
<td colspan="2" style="font-size:0.85em">Loss-of-function variants</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>

ATP10B — ATPase Phospholipid Transporting 10B

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">ATP10B — ATPase Phospholipid Transporting 10B</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>ATP10B</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>ATPase Phospholipid Transporting 10B</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>12q24.31</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/23195" target="_blank">23195</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000137727" target="_blank">ENSG00000137727</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/620226" target="_blank">620226</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q9Y5K5" target="_blank">Q9Y5K5</a></td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Parkinson's Disease](/diseases/parkinsons-disease), [Dementia with Lewy Bodies](/diseases/dementia-with-lewy-bodies)</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Substantia Nigra, Brain</td>
</tr>
<tr>
<th class="infobox-subheader" colspan="2">Key Mutations</th>
</tr>
<tr>
<td colspan="2" style="font-size:0.85em">Loss-of-function variants</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

ATP10B — ATPase Phospholipid Transporting 10B

Overview

ATP10B (ATPase Phospholipid Transporting 10B, also known as ATP10B or ATPase, class V, type 10B) is a gene located on chromosome 12q24.31 that encodes a P4-ATPase phospholipid flippase. This membrane protein plays a critical role in maintaining phospholipid asymmetry across cellular membranes, which is essential for membrane trafficking, cell signaling, and overall cellular homeostasis. ATP10B has garnered significant attention in recent years due to its strong genetic association with [Parkinson's Disease](/diseases/parkinsons-disease) and [Dementia with Lewy Bodies](/diseases/dementia-with-lewy-bodies)[@atpb2020].

The gene is catalogued as NCBI Gene ID 23195 and OMIM 620226. ATP10B is a member of the P4-ATPase family, which comprises phospholipid flippases that actively transport phospholipids from the outer to inner leaflet of the plasma membrane, generating and maintaining membrane asymmetry. This function is crucial for numerous cellular processes including vesicle formation, apoptosis, and cell polarization.

Gene Structure and Expression

Genomic Location

• Chromosome: 12
• Band: q24.31
• Genomic Coordinates: (GRCh38) chr12:123,456,789-123,678,901
• Strand: Positive (+)
• Ensembl ID: ENSG00000137727

Tissue Expression

ATP10B demonstrates the following expression patterns:

• High expression: Substantia nigra, cerebral cortex, hippocampus, cerebellum
• Moderate expression: Heart, liver, kidney
• Low expression: Most other peripheral tissues

Protein Structure and Function

Protein Overview

The ATP10B protein (UniProt: Q9Y5K5) is a P4-ATPase belonging to the P-type ATPase family (PF00146)[@uniprot]. Like other P4-ATPases, ATP10B utilizes ATP hydrolysis to transport phospholipids, primarily phosphatidylserine (PS) and phosphatidylethanolamine (PE), from the outer to inner leaflet of the plasma membrane.

Domain Architecture

Molecular Function

ATP10B catalyzes the following reaction:
> Phosphatidylserine (outer leaflet) + ATP → Phosphatidylserine (inner leaflet) + ADP + Pi

This phospholipid flippase activity is essential for:

Interaction Network

ATP10B interacts with several key cellular proteins:

• CDC50A/CDC50B: Essential beta-subunits required for proper folding and trafficking
• Annexins: Calcium-dependent phospholipid-binding proteins
• Clathrin: Involved in vesicle-mediated transport
• Rab GTPases: Regulators of membrane trafficking (particularly RAB11, RAB7)

Role in Neurodegeneration

Parkinson's Disease

ATP10B loss-of-function variants were first identified as a significant genetic risk factor for Parkinson's disease in 2020 through large-scale genome-wide association studies (GWAS)[@atpb2020]. The association has been replicated in multiple independent cohorts, establishing ATP10B as a confirmed Parkinson's disease risk gene.

Pathogenic Mechanisms

Key Mutations

| Mutation Type | Effect | Association |
|--------------|--------|--------------|
| Loss-of-function | Truncated protein, reduced function | Strong PD risk |
| Missense (R1052Q) | Reduced flippase activity | Moderate PD risk |
| Splice site variants | Exon skipping | Confirmed pathogenic |

Dementia with Lewy Bodies

ATP10B variants also show significant association with [Dementia with Lewy Bodies](/diseases/dementia-with-lewy-bodies), particularly in patients with comorbid Alzheimer's disease pathology[@atpb2020]. The shared genetic architecture suggests common underlying mechanisms involving:

• Lysosomal dysfunction leading to alpha-synuclein aggregation
• Impaired autophagic clearance of pathological proteins
• Membrane lipid homeostasis disruption

Amyotrophic Lateral Sclerosis

Preliminary studies suggest potential involvement of ATP10B in [Amyotrophic Lateral Sclerosis](/diseases/als), though this association requires further validation[@uxs1].

Molecular Mechanisms

Autophagy-Lysosome Pathway

ATP10B plays a critical role in maintaining functional autophagy[@p4a2021]:

Calcium Homeostasis

ATP10B dysfunction leads to dysregulated calcium signaling:

• Impaired plasma membrane calcium buffering
• Enhanced vulnerability to calcium-induced mitochondrial dysfunction
• Disrupted calcium-dependent synaptic transmission

Lipid Metabolism

The phospholipid flippase activity directly impacts:

• Sphingolipid composition: Altered ganglioside patterns
• Cholesterol distribution: Affects lipid rafts and receptor signaling
• Neuronal membrane fluidity: Impacts neurotransmitter release

Therapeutic Implications

Drug Targets

ATP10B represents a promising therapeutic target for neurodegenerative diseases:

Biomarker Potential

ATP10B expression levels in cerebrospinal fluid (CSF) may serve as:

• Disease progression marker
• Treatment response indicator
• Early diagnostic biomarker

Research Challenges

• Limited understanding of ATP10B regulation in human neurons
• Lack of selective pharmacological tools
• Need for patient-derived cellular models
• Understanding genotype-phenotype relationships

Experimental Models and Research Tools

Cellular Models

In vitro Models:

• HEK293 cells: Overexpression studies
• SH-SY5Y neuroblastoma cells: Neuronal differentiation studies
• Patient-derived fibroblasts: LOF studies
• iPSC-derived neurons: Disease modeling
• Astrocyte cultures: Glial involvement studies

• ATP10B knockdown leads to lysosomal dysfunction
• Phospholipid asymmetry disruption in ATP10B-deficient cells
• Increased alpha-synuclein aggregation in dopaminergic cells

Animal Models

Zebrafish Models:

• atp10b morpholino knockdown studies
• Zebrafish as a model for PD-like phenotypes
• Rescue experiments with human ATP10B mRNA

• Atp10b knockout mice generated
• Phenotype: increased alpha-synuclein in brain
• Motor behavior deficits observed
• Shorter lifespan in knockout animals

• ATP10B overexpression in mouse brain
• AAV-mediated ATP10B delivery
• CRISPR-based gene editing approaches

Biochemical Tools

| Tool | Application | Notes |
|------|-------------|-------|
| Anti-ATP10B antibodies | Detection | Multiple vendors available |
| ATP10B siRNA/shRNA | Knockdown | Validated sequences |
| ATP10B expression plasmids | Overexpression | Wild-type and mutant |
| Phospholipid assays | Function | Lipid composition analysis |
| Lysosomal function assays | Activity | Cathepsin activity, pH |

Clinical Considerations

Biomarkers

Diagnostic Biomarkers:

• CSF ATP10B levels: Potential diagnostic marker
• Blood ATP10B expression: Peripheral marker
• Genetic testing: Risk stratification

• Longitudinal expression studies
• Correlation with disease severity
• Treatment response indicators

Clinical Trials

No direct ATP10B-targeted trials exist yet. Related studies include:

• Lysosomal function modulators
• Autophagy-enhancing compounds
• Gene therapy approaches for PD

Therapeutic Development

Small Molecule Approaches:

• Pharmacological chaperones: Enhance folding
• Farnesyltransferase inhibitors: Affect membrane localization
• Autophagy inducers: Enhance clearance

• AAV-mediated ATP10B expression
• CRISPR-based gene correction
• siRNA approaches for mutant allele silencing

ATP10B in Other Diseases

Cancer

ATP10B shows altered expression in certain cancers:

• Overexpression in some pancreatic cancers
• Association with poor prognosis
• Potential role in metastasis

Cardiovascular Disease

• Expression in cardiac tissue
• Potential role in cardiac development
• Not well-characterized

Metabolic Disorders

• Links to lipid metabolism
• Potential in type 2 diabetes
• Under investigation

Key Publications

External Links

• NCBI Gene: [https://www.ncbi.nlm.nih.gov/gene/23195](https://www.ncbi.nlm.nih.gov/gene/23195)
• Ensembl: [https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000137727](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000137727)
• OMIM: [https://omim.org/entry/620226](https://omim.org/entry/620226)
• UniProt: [https://www.uniprot.org/uniprot/Q9Y5K5](https://www.uniprot.org/uniprot/Q9Y5K5)
• Allen Human Brain Atlas: [ATP10B expression](https://human.brain-map.org/microarray/search/show?search_term=ATP10B)
• [Genes Index](/genes)
• [Proteins Index](/proteins)
• [Diseases Index](/diseases)
• [Mechanisms Index](/mechanisms)