ArticleHuman molecular genetics2014
Parkinson's disease-associated human ATP13A2 (PARK9) deficiency causes zinc dyshomeostasis and mitochondrial dysfunction.
Article in Human molecular genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 96 papers.
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Who cites it
96 citing papers in PubMed, 148 citations in OpenAlex.
- Improved Parkinsons disease motor score in a single-arm open-label trial of febuxostat and inosine.Medicine · 2020Trial
- Clinical Evaluation of Three KRS Families and Cellular Analysis of Distinct ATP13A2 Mutations Reveal Different Levels of Iron Accumulation.Journal of neurochemistry · 2026Article
- The role of energy deficit in autophagy failure in Parkinson's disease.Frontiers in aging neuroscience · 2026Review
- ATP13A2 promoted cell stemness, cisplatin resistance, autophagy, and cell progression of bladder cancer.Frontiers in immunology · 2026Article
- Bridging the gap in Parkinson's disease research: from general pathophysiology to advanced 3d cell culture models.Cell communication and signaling : CCS · 2025Review
- Phenotypic characterization of an Atp13a2 knockout rat model of Parkinson's disease.NPJ Parkinson's disease · 2025Article
- IntravenousJournal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology · 2025Article
- A TRPM2-Driven Signalling Cycle Orchestrates Abnormal Inter-Organelle Crosstalk in Cardiovascular and Metabolic Diseases.Biomolecules · 2025Review
- Parkinson Disease Signaling Pathways, Molecular Mechanisms, and Potential Therapeutic Strategies: A Comprehensive Review.International journal of molecular sciences · 2025Review
- Inter-Organelle Crosstalk in Oxidative Distress: A Unified TRPM2-NOX2 Mediated Vicious Cycle Involving CaAntioxidants (Basel, Switzerland) · 2025Review
- Impaired Mitochondrial Function and Ubiquitin Proteasome System Activate α-Synuclein Aggregation in Zinc-Induced Neurotoxicity: Effect of Antioxidants.Journal of molecular neuroscience : MN · 2025Article
- Homeostasis and metabolism of iron and other metal ions in neurodegenerative diseases.Signal transduction and targeted therapy · 2025Review
- Targeting the Interplay Between Autophagy and the Nrf2 Pathway in Parkinson's Disease with Potential Therapeutic Implications.Biomolecules · 2025Review
- Mitochondrial Dysfunction: A Key Player in Brain Aging and Diseases.Current issues in molecular biology · 2024Review
- Olfactory dysfunction and its related molecular mechanisms in Parkinson's disease.Neural regeneration research · 2024Review
- The role of mitochondrial dynamics in disease.MedComm · 2023Review
- Zinc and Central Nervous System Disorders.Nutrients · 2023Review
- Signaling pathways in Parkinson's disease: molecular mechanisms and therapeutic interventions.Signal transduction and targeted therapy · 2023Review
- On the Chemical and Biological Characteristics of Multifunctional Compounds for the Treatment of Parkinson's Disease.Antioxidants (Basel, Switzerland) · 2023Review
- ATP13A2 Gene Silencing in Drosophila Affects Autophagic Degradation of A53T Mutant α-Synuclein.International journal of molecular sciences · 2023Article
36 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Human ATP13A2 (PARK9), a lysosomal type 5 P-type ATPase, has been associated with autosomal recessive early-onset Parkinson's disease (PD). ATP13A2 encodes a protein that is highly expressed in neurons and is predicted to function as a cation pump, although the substrate specificity remains unclear. Accumulation of zinc and mitochondrial dysfunction are established aetiological factors that contribute to PD; however, their underlying molecular mechanisms are largely unknown. Using patient-derived human olfactory neurosphere cultures, which harbour loss-of-function mutations in both alleles of ATP13A2, we identified a low intracellular free zinc ion concentration ([Zn(2+)]i), altered expression of zinc transporters and impaired sequestration of Zn(2+) into autophagy-lysosomal pathway-associated vesicles, indicating that zinc dyshomeostasis occurs in the setting of ATP13A2 deficiency. Pharmacological treatments that increased [Zn(2+)]i also induced the production of reactive oxygen species and aggravation of mitochondrial abnormalities that gave rise to mitochondrial depolarization, fragmentation and cell death due to ATP depletion. The toxic effect of Zn(2+) was blocked by ATP13A2 overexpression, Zn(2+) chelation, antioxidant treatment and promotion of mitochondrial fusion. Taken together, these results indicate that human ATP13A2 deficiency results in zinc dyshomeostasis and mitochondrial dysfunction. Our data provide insights into the molecular mechanisms of zinc dyshomeostasis in PD and its contribution to mitochondrial dysfunction with ATP13A2 as a molecular link between the two distinctive aetiological factors of PD.
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