ArticleParkinson's disease2016
Protection against Mitochondrial and Metal Toxicity Depends on Functional Lipid Binding Sites in ATP13A2.
Article in Parkinson's disease, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 27 citations in OpenAlex.
- Article
- Mechanism of phosphoinositide regulation of lysosomal pH via inhibition of CLC-7.bioRxiv : the preprint server for biology · 2025Article
- Nigral ATP13A2 depletion induces Parkinson's disease-related neurodegeneration in a pilot study in non-human primates.NPJ Parkinson's disease · 2024Article
- ATP13A2 (PARK9) and basal ganglia function.Frontiers in neurology · 2023Review
- ATP13A2 protects dopaminergic neurons in Parkinson's disease: from biology to pathology.Journal of biomedical research · 2022Article
- Cryo-EM structures and transport mechanism of human P5B type ATPase ATP13A2.Cell discovery · 2021Article
- ATP13A2-mediated endo-lysosomal polyamine export counters mitochondrial oxidative stress.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Mutated ATP10B increases Parkinson's disease risk by compromising lysosomal glucosylceramide export.Acta neuropathologica · 2020Article
- Toxic-Metal-Induced Alteration in miRNA Expression Profile as a Proposed Mechanism for Disease Development.Cells · 2020Review
- Article
- Role of Astrocytes in Manganese Neurotoxicity Revisited.Neurochemical research · 2019Review
- The Role of Lipids in Parkinson's Disease.Cells · 2019Review
- HDAC6 is a therapeutic target in mutant GARS-induced Charcot-Marie-Tooth disease.Brain : a journal of neurology · 2018Article
- Article
- Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78).Brain : a journal of neurology · 2017Article
- ATP13A3 is a major component of the enigmatic mammalian polyamine transport system.The Journal of biological chemistryArticle
Corrections and comments
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The late endo-/lysosomal P-type ATPase ATP13A2 (PARK9) is implicated in Parkinson's disease (PD) and Kufor-Rakeb syndrome, early-onset atypical Parkinsonism. ATP13A2 interacts at the N-terminus with the signaling lipids phosphatidic acid (PA) and phosphatidylinositol (3,5) bisphosphate (PI(3,5)P2), which modulate ATP13A2 activity under cellular stress conditions. Here, we analyzed stable human SHSY5Y cell lines overexpressing wild-type (WT) or ATP13A2 mutants in which three N-terminal lipid binding sites (LBS1-3) were mutated. We explored the regulatory role of LBS1-3 in the cellular protection by ATP13A2 against mitochondrial stress induced by rotenone and found that the LBS2-3 mutants displayed an abrogated protective effect. Moreover, in contrast to WT, the LBS2 and LBS3 mutants responded poorly to pharmacological inhibition of, respectively, PI(3,5)P2 and PA formation. We further demonstrate that PA and PI(3,5)P2 are also required for the ATP13A2-mediated protection against the toxic metals Mn(2+), Zn(2+), and Fe(3+), suggesting a general lipid-dependent activation mechanism of ATP13A2 in various PD-related stress conditions. Our results indicate that the ATP13A2-mediated protection requires binding of PI(3,5)P2 to LBS2 and PA to LBS3. Thus, targeting the N-terminal lipid binding sites of ATP13A2 might offer a therapeutic approach to reduce cellular toxicity of various PD insults including mitochondrial stress.
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Registered trials
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