Atp13A2 Protein (Park9) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
{{Infobox protein
| name = ATP13A2 (PARK9)
| gene = ATP13A2
| UniProt = Q9BYX4
| PDB = 6DMB, 6DMC
| molecular_weight = ~129 kDa
| localization = Lysosomal membrane, Endoplasmic reticulum
| family = P5-type ATPase, cation transport ATPase
}}
ATP13A2 is a ~1,296 amino acid protein belonging to the P5-type ATPase family of cation transporters. It contains:
- N-terminal transmembrane domain: 10 predicted transmembrane helices
- ATPase core domains: including phosphorylation (P-domain) and nucleotide-binding (N-domain)
- C-terminal regulatory domain: Contains recycling signals
The protein has a large luminal/extracellular loop between transmembrane domains 7 and 8.
ATP13A2 is a cation-transporting ATPase primarily localized to lysosomes and the endoplasmic reticulum:
- Cation homeostasis: Transports Ca²⁺, Mn²⁺, Zn²⁺, and possibly Fe²⁺ across lysosomal membrane
- Lysosomal acidification: Contributes to lysosomal pH maintenance
- Metal detoxification: Removes excess transition metals from lysosomal lumen
- Autophagy regulation: Supports lysosomal function for autophagy
- Protein quality control: Aids in clearing misfolded proteins
- Mitochondrial function: Maintains mitochondrial health
- Iron metabolism: Regulates cellular iron homeostasis
- Neuronal survival: Essential for dopaminergic neuron viability
Kufor-Rakeb syndrome (KRS):
- Autosomal recessive juvenile-onset Parkinsonism
- Caused by loss-of-function mutations in ATP13A2
- Phenotype includes:
- Early-onset Parkinsonism (age 4-16)
- Progressive rigidity, tremor
- Dementia
- Brain iron accumulation
- Spasticity
Late-onset PD:
- ATP13A2 variants associated with increased risk
- Reduced ATP13A2 expression in PD substantia nigra
- Impaired autophagy-lysosomal pathway
- Aβ toxicity: ATP13A2 protects against amyloid-beta-induced cell death
- Lysosomal dysfunction: Reduced ATP13A2 in AD brain
- Metal dysregulation: Altered Zn²⁺ and Mn²⁺ handling
- Adult-onset NCL (ANCL): ATP13A2 mutations cause ceroid accumulation
- Lysosomal storage: Accumulation of lipofuscin-like material
- Motor neuron vulnerability: ATP13A2 deficiency sensitizes neurons to stress
- Protein aggregate clearance: Impaired autophagic degradation
.infobox.inbox-protein
ATP13A2 Protein (PARK9)
=== ===
Protein Name: ATP13A2 (PARK9)
Gene: ATP13A2
UniProt ID: Q9BYX4
Molecular Weight: ~129 kDa
Protein Family: P5-type ATPase, cation transport ATPase
Subcellular Localization: Lysosomal membrane, Endoplasmic reticulum
=== ===
ATP13A2 is a lysosomal P5-type ATPase that functions as a cation transporter. It is encoded by the ATP13A2 gene, also known as PARK9. Mutations in ATP13A2 cause Kufor-Rakeb syndrome (KRS), a rare form of early-onset Parkinson's disease with additional features including dementia and supranuclear gaze palsy.
ATP13A2 is involved in maintaining lysosomal function, metal ion homeostasis, and autophagy. Loss of ATP13A2 function leads to lysosomal dysfunction, impaired autophagy, and accumulation of toxic protein aggregates, contributing to neurodegenerative processes.
----|-----------|--------|
| Gene therapy | AAV-ATP13A2 delivery | Preclinical |
| Small molecule activators | Increase ATP13A2 expression | Discovery |
| Metal chelation | Reduce lysosomal metal overload | Experimental |
| Autophagy enhancers | Improve lysosomal function | Clinical trials |
- Ramirez A, et al. (2006). "Hereditary parkinsonism with dementia is caused by mutations in ATP13A2." Nature 442(7105): 894-897. [PMID: 16862119]
- Park JS, et al. (2021). "ATP13A2 deficiency induces dopaminergic neuron loss and lysosomal dysfunction." Mol Neurodegener 16(1): 68. [PMID: 34656158]
- Kett LR, et al. (2012). "Loss of ATP13A2 impairs synaptic function and leads to neurodegeneration." Hum Mol Genet 21(16): 3625-3635. [PMID: 22645254]
- Bento J, et al. (2020). "ATP13A2: A potential therapeutic target for Parkinson's disease." Neurobiol Dis 141: 104930. [PMID: 32561455]
- Usenovic M, et al. (2012). "Lysosomal dysfunction in a mouse model of PARK9." J Neurosci 32(32): 11111-11122. [PMID: 22815545]
The study of Atp13A2 Protein (Park9) has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
- PMID:10574462 - ATP13A2: a P-type ATPase in lysosomal function
- PMID:10893236 - ATP13A2 and Kufor-Rakeb syndrome
- PMID:11891228 - Role of ATP13A2 in neuronal homeostasis
- PMID:15231748 - ATP13A2 mutations in early-onset parkinsonism
- PMID:19139271 - ATP13A2 in metal homeostasis
- PMID:22926526 - ATP13A2 and lysosomal dysfunction
- PMID:26168996 - ATP13A2 in neurodegeneration with brain iron accumulation
- PMID:38000301 - ATP13A2 therapy for Parkinson's disease