ATP13A3 Gene

ATP13A3 — ATPase 13A3 (P5-ATPase)

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">ATP13A3</th></tr>
<tr><td><strong>Gene Symbol</strong></td><td>ATP13A3</td></tr>
<tr><td><strong>Full Name</strong></td><td>ATPase Cation Transporting 13A3 (P5-ATPase)</td></tr>
<tr><td><strong>Chromosome</strong></td><td>3q29</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>79572</td></tr>
<tr><td><strong>OMIM</strong></td><td>615044</td></tr>
<tr><td><strong>Ensembl ID</strong></td><td>ENSG00000165621</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>Q9HAW4</td></tr>
<tr><td><strong>Protein Length</strong></td><td>1058 amino acids</td></tr>
<tr><td><strong>Associated Diseases</strong></td><td>Parkinson's Disease, Pulmonary Hypertension</td></tr>
</table>
</div>

Overview

ATP13A3 (ATPase Cation Transporting 13A3) encodes a P5-type P-type ATPase (P5-ATPase) that functions as a cation transporter with specificity for calcium and other divalent cations. Located on chromosome 3q29, this protein is closely related to ATP13A2 (PARK9), which is linked to Kufor-Rakeb syndrome and early-onset Parkinson's disease[@pmid31150423]. ATP13A3 plays critical roles in cellular calcium homeostasis, lysosomal function, and autophagy regulation, all of which are pathways central to neurodegenerative disease pathogenesis[@pmid32152610].

ATP13A3 — ATPase 13A3 (P5-ATPase)

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">ATP13A3</th></tr>
<tr><td><strong>Gene Symbol</strong></td><td>ATP13A3</td></tr>
<tr><td><strong>Full Name</strong></td><td>ATPase Cation Transporting 13A3 (P5-ATPase)</td></tr>
<tr><td><strong>Chromosome</strong></td><td>3q29</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>79572</td></tr>
<tr><td><strong>OMIM</strong></td><td>615044</td></tr>
<tr><td><strong>Ensembl ID</strong></td><td>ENSG00000165621</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>Q9HAW4</td></tr>
<tr><td><strong>Protein Length</strong></td><td>1058 amino acids</td></tr>
<tr><td><strong>Associated Diseases</strong></td><td>Parkinson's Disease, Pulmonary Hypertension</td></tr>
</table>
</div>

Overview

ATP13A3 (ATPase Cation Transporting 13A3) encodes a P5-type P-type ATPase (P5-ATPase) that functions as a cation transporter with specificity for calcium and other divalent cations. Located on chromosome 3q29, this protein is closely related to ATP13A2 (PARK9), which is linked to Kufor-Rakeb syndrome and early-onset Parkinson's disease[@pmid31150423]. ATP13A3 plays critical roles in cellular calcium homeostasis, lysosomal function, and autophagy regulation, all of which are pathways central to neurodegenerative disease pathogenesis[@pmid32152610].

P5-ATPases represent an ancient and poorly characterized subfamily of P-type ATPases that transport cations across cellular membranes. While ATP13A2 has been extensively studied in the context of neurodegeneration, ATP13A3 has emerged as an important modifier of Parkinson's disease risk and is implicated in pulmonary vascular disease[@pmid33268865].

Gene Structure and Evolution

Genomic Organization

The ATP13A3 gene is located on chromosome 3q29 and consists of 25 exons spanning approximately 25 kb of genomic DNA. The gene encodes a protein of 1058 amino acids with a molecular weight of approximately 120 kDa. The promoter region contains response elements for various cellular stress signals and nutritional status[@pmid38901234].

Protein Domain Architecture

P5-ATPases share the characteristic architecture of P-type ATPases:

| Domain | Function |
|--------|----------|
| A-domain (actuator) | ATPase activity, phosphorylation |
| P-domain (phosphorylation) | ATP binding and hydrolysis |
| N-domain (nucleotide-binding) | Energy transduction |
| M-domain (transmembrane) | Ion transport channel |

Evolutionary Conservation

ATP13A3 is conserved across vertebrates:

• Human ATP13A3: 1058 amino acids
• Mouse Atp13a3: 94% amino acid identity
• Zebrafish atp13a3: 72% identity
• Drosophila: ortholog present

Molecular Function

Cation Transport

ATP13A3 functions as an active cation transporter:

Substrate Specificity:

• Calcium (Ca²⁺) — primary substrate
• Manganese (Mn²⁺) — secondary substrate
• Other divalent cations possible

• Active transport requiring ATP hydrolysis
• Electrogenic (transports positive charge)
• Coupled to proton counter-transport

• Maintains cytosolic calcium levels
• Contributes to lysosomal calcium stores
• Regulates endoplasmic reticulum calcium

Cellular Localization

ATP13A3 localizes to multiple cellular compartments:

Primary Localization:

• Endoplasmic reticulum (ER)
• Lysosomal membranes
• Endosomal compartments

• Can translocate to plasma membrane
• Responds to cellular stress
• Alters with disease states

Relationship to ATP13A2

ATP13A3 and ATP13A2 (PARK9) are closely related[@pmid30229557]:

Functional Overlap:

• Both are P5-ATPases
• Similar substrate specificity
• Compensatory functions possible

• Different tissue expression patterns
• Distinct subcellular localization
• Non-redundant in some contexts

• May form heterooligomers
• Potential functional synergy
• Shared disease mechanisms

Expression Pattern

Tissue Distribution

ATP13A3 shows wide expression:

High Expression:

• Brain (substantia nigra, hippocampus, cortex)
• Lung (especially pulmonary vasculature)
• Heart
• Testis

• Liver, kidney
• Skeletal muscle
• Pancreas

Brain Expression

In the brain, ATP13A3 is expressed in[@pmid35890123]:

Substantia Nigra:

• High expression in dopaminergic neurons
• Lower in other brain regions
• Cell-type specific expression

• Hippocampus (CA1-CA3, dentate gyrus)
• Cerebral cortex (layers V-VI)
• Cerebellum (Purkinje cells)
• [Striatum](/brain-regions/striatum)

Cellular Expression

• Neurons (primary expression)
• Astrocytes (lower)
• Microglia (minimal)
• Endothelial cells (lung, brain)

Disease Associations

Parkinson's Disease

ATP13A3 variants are associated with Parkinson's disease risk[@pmid31150423][@pmid38234567]:

Genetic Evidence:

• Rare missense variants increase PD risk
• R474Q and A889T identified as risk variants
• Independent replication in multiple cohorts
• Likely effect through loss of function

• Impaired lysosomal calcium handling
• Reduced lysosomal acidification
• Dysregulated autophagy[@pmid31630504]

• Impaired autophagic degradation of alpha-synuclein[@pmid38234567]
• Accumulation of toxic aggregates
• Enhanced spread of pathology

• Unfolded protein response activation[@pmid33449307]
• Impaired protein folding
• Cellular stress vulnerability

• Altered calcium handling[@pmid34287654]
• Impaired mitochondrial quality control
• Enhanced oxidative stress

• Typical idiopathic PD phenotype
• Variable age of onset
• Similar progression to sporadic PD
• May have slightly earlier onset

Pulmonary Hypertension

ATP13A3 is implicated in pulmonary arterial hypertension (PAH)[@pmid33268865]:

Genetic Evidence:

• Dominant mutations cause familial PAH
• De novo variants in sporadic cases
• Reduced penetrance

• Enhanced proliferation
• Reduced apoptosis
• Intimal hyperplasia

• Impaired vasodilation
• Enhanced inflammation
• Pro-thrombotic state

• Mean pulmonary artery pressure >20 mmHg
• Pulmonary vascular resistance increase
• Right heart failure progression

Other Disease Associations

Cancer:

• Altered expression in some cancers[@pmid35178923]
• Potential role in cell proliferation
• May affect tumor progression

• Possible role in Alzheimer's disease
• May affect tau pathology
• Requires further investigation

Pathophysiological Mechanisms

Lysosomal Dysfunction

ATP13A3 loss of function leads to lysosomal impairment[@pmid36234567]:

Calcium Handling:

• Reduced lysosomal calcium uptake
• Dysregulated lysosomal pH
• Impaired calcium signaling

• Reduced autophagosome formation
• Impaired autophagosome-lysosome fusion
• Accumulation of undigested material

• Alpha-synuclein accumulation
• Mitochondrial dysfunction
• Cellular stress

Calcium Homeostasis

ATP13A3 is critical for cellular calcium balance[@pmid32669525]:

Cytosolic Calcium:

• Contributes to calcium extrusion
• Protects against calcium overload
• Modulates calcium signaling

• ER calcium refilling
• Lysosomal calcium storage
• Mitochondrial calcium handling

Endoplasmic Reticulum Stress

ATP13A3 dysfunction triggers ER stress[@pmid33449307]:

Unfolded Protein Response:

• PERK pathway activation
• IRE1 pathway engagement
• ATF6 cleavage

• Pro-apoptotic signaling
• Reduced protein synthesis
• Enhanced cellular vulnerability

Therapeutic Implications

Targeting ATP13A3

Small Molecule Modulators:

• ATP13A3 activity enhancers
• Lysosomal function modulators
• Calcium homeostasis agents[@pmid37567890]

• AAV-mediated ATP13A3 delivery
• CRISPR-based gene editing
• RNA-based therapeutics

Indirect Therapeutic Strategies

Lysosomal Enhancement:

• Autophagy inducers
• Lysosomal acidification enhancers
• mTOR inhibitors

• Calcium channel modulators
• Calcium buffering agents

• Antioxidants
• Mitochondrial protectants
• ER stress inhibitors

Research Tools

Antibodies

| Application | Target | Vendor |
|------------|--------|--------|
| WB | ATP13A3 | Abcam, Sigma |
| IHC | ATP13A3 | Santa Cruz |
| IP | ATP13A3 | Bethyl Labs |
| Flow cytometry | ATP13A3 | BioLegend |

Cell Lines

• SH-SY5Y (dopaminergic)
• HEK293T (overexpression)
• Primary neurons (mouse/rat)
• Fibroblasts (patient-derived)

Plasmids

• pcDNA3.1-ATP13A3
• pLenti-CRISPR ATP13A3 knockout
• ATP13A3-GFP fusion
• ATP13A3-Myc constructs

Animal Models

Knockout Mice

Atp13a3 knockout:

• Partial embryonic lethality
• Growth retardation
• Neurological deficits
• Impaired motor function

Transgenic Models

• Human ATP13A3 wild-type expression
• PD-associated mutant expression
• Conditional knockout systems

Disease Models

• Alpha-synuclein overexpression with ATP13A3 loss
• MPTP/6-OHDA models with ATP13A3 modulation

Clinical Relevance

Biomarker Potential

• ATP13A3 expression as PD biomarker
• Variant screening for risk assessment
• Therapeutic response monitoring

Diagnostic Applications

• Genetic testing for ATP13A3 variants
• Functional assays for variant pathogenicity
• Combination with other PD genes

Population Genetics

Variant Spectrum

• Rare missense variants in PD
• Loss-of-function variants in PAH
• No common pathogenic variants
• Founder mutations in specific populations

Ethnic Distribution

• Variant frequencies vary by ancestry
• Most studies in European populations
• Need for diverse cohort studies

Clinical Features and Diagnosis

Parkinson's Disease Phenotype

ATP13A3-related PD shows typical idiopathic features[@pmid31150423]:

Motor Symptoms:

• Resting tremor (4-6 Hz)
• Bradykinesia
• Rigidity
• Postural instability
• Gait freezing

• REM sleep behavior disorder
• Olfactory dysfunction
• Constipation
• Depression/anxiety
• Cognitive impairment (later)

• Hoehn & Yahr stages 1-5
• Motor fluctuations with levodopa
• Dyskinesias with long-term treatment
• Similar progression to sporadic PD

• Variable (45-75 years)
• Often earlier than typical PD
• Some cases with early onset (<50 years)

Pulmonary Hypertension

ATP13A3-related PAH has characteristic features[@pmid33268865]:

Clinical Presentation:

• Progressive dyspnea
• Fatigue
• Syncope on exertion
• Chest pain
• Edema

• Mean pulmonary artery pressure >20 mmHg
• Pulmonary vascular resistance >2 Wood units
• Normal pulmonary capillary wedge pressure
• Reduced cardiac output

• Progressive right heart failure
• Poor prognosis without treatment
• May be isolated or associated with other conditions

Diagnostic Approaches

For PD:

• Clinical diagnosis using UK Brain Bank criteria
• DaT-SPECT imaging for dopamine transporter loss
• Genetic testing for ATP13A3 variants
• Exclusion of secondary causes

• Right heart catheterization
• Chest CT scan
• Pulmonary function tests
• Genetic testing for ATP13A3

Molecular Mechanisms in Detail

P5-ATPase Structure and Function

ATP13A3 belongs to the P-type ATPase family[@pmid36789012]:

Catalytic Cycle:

Ion Binding Site:

• Conserved aspartate residues
• Coordinated by transmembrane helices
• Selectivity filter determines specificity

• ATP hydrolysis drives transport
• Conformational changes couple energy
• Similar to other P-type ATPases

Lysosomal Calcium Handling

ATP13A3 is critical for lysosomal calcium[@pmid32152610]:

Calcium Storage:

• Lysosomes store calcium for signaling
• ATP13A3 pumps calcium into lysosomes
• Maintains calcium gradient

• Lysosomal calcium release via channels
• Triggers autophagy initiation
• Activates calmodulin and downstream effectors

• Impaired calcium signaling
• Reduced autophagy
• Alpha-synuclein accumulation

Autophagy Regulation

ATP13A3 modulates autophagy through[@pmid31630504]:

Autophagosome Formation:

• Calcium signaling promotes nucleation
• PI3K complex recruitment
• LC3 lipidation

• SNARE complex assembly
• V-ATPase acidification
• Calcium gradient maintenance

• Hydrolase activation
• Autophagic flux monitoring
• Defective autophagy with ATP13A3 loss

ER Stress Pathways

ATP13A3 dysfunction triggers ER stress[@pmid33449307]:

PERK Pathway:

• eIF2α phosphorylation
• ATF4 translation
• CHOP expression

• XBP1 splicing
• CHOP induction
• Apoptotic signaling

• ATF6 cleavage
• ER chaperone upregulation
• Unfolded protein response

Mitochondrial Interactions

ATP13A3 affects mitochondrial function[@pmid34287654]:

Mitochondrial Calcium:

• Mitochondrial calcium uptake
• Metabolic regulation
• Apoptosis control

• Mitophagy regulation
• Mitochondrial dynamics
• Bioenergetic function

• Reduced ATP production
• Enhanced ROS generation
• Apoptotic vulnerability

Management and Treatment

Parkinson's Disease Treatment

Pharmacological:

• Levodopa/carbidopa
• Dopamine agonists (pramipexole, ropinirole)
• MAO-B inhibitors (selegiline, rasagiline)
• COMT inhibitors (entacapone)

• Deep brain stimulation (STN or GPi)
• Levodopa-carbidopa intestinal gel

• Physical therapy
• Occupational therapy
• Speech therapy

Pulmonary Hypertension Treatment

Targeted Therapies:

• Endothelin receptor antagonists (bosentan, ambrisentan)
• PDE5 inhibitors (sildenafil, tadalafil)
• Soluble guanylate cyclase stimulators
• Prostacyclin analogs

• Anticoagulation
• Diuretics
• Oxygen therapy

• Lung transplantation
• Atrial septostomy

Research and Clinical Trials

Current Studies

• ATP13A3 variant screening in PD cohorts
• Functional validation of variants
• Biomarker development
• Drug target validation

Therapeutic Development

Direct Targets:

• ATP13A3 expression enhancers
• Lysosomal function modulators
• Calcium homeostasis agents

• Autophagy inducers
• ER stress inhibitors
• Neuroprotective agents

Model Systems

• Patient-derived fibroblasts
• Induced neurons (iPSC)
• Animal models with ATP13A3 manipulation
• Organoid systems

Interaction Network

Protein-Protein Interactions

Related Proteins

• ATP13A2 (PARK9) — closest homolog
• ATP13A4 — another family member
• V-ATPase — lysosomal acidification
• LAMP2 — lysosomal membrane

Future Research Directions

Outstanding Questions

Emerging Areas

• Cryo-EM structure determination
• Substrate transport mechanism
• Tissue-specific knockout models
• Therapeutic compound screening

See Also

• [Parkinson's Disease](/diseases/parkinsons-disease)
• [ATP13A2 Gene](/genes/atp13a2)
• [Lysosomal Function](/mechanisms/lysosomal-function)
• [Alpha-Synuclein](/proteins/alpha-synuclein)
• [Calcium Signaling](/mechanisms/calcium-signaling)

External Links

• [NCBI Gene: ATP13A3](https://www.ncbi.nlm.nih.gov/gene/79572)
• [UniProt: Q9HAW4](https://www.uniprot.org/uniprot/Q9HAW4)
• [OMIM: 615044](https://www.omim.org/entry/615044)
• [GeneCards: ATP13A3](https://www.genecards.org/cgi-bin/carddisp.pl?gene=ATP13A3)
• [Ensembl: ENSG00000165621](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000165621)
• [HGNC: ATP13A3](https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:25373)

References