ArticleProceedings of the National Academy of Sciences of the United States of America2015
A lipid switch unlocks Parkinson's disease-associated ATP13A2.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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Who cites it
57 citing papers in PubMed, 95 citations in OpenAlex.
- ATP13A4 gates extracellular polyamine levels to control excitatory synaptogenesis.Nature communications · 2026Article
- Clinical Evaluation of Three KRS Families and Cellular Analysis of Distinct ATP13A2 Mutations Reveal Different Levels of Iron Accumulation.Journal of neurochemistry · 2026Article
- Mechanism of phosphoinositide regulation of lysosomal pH via inhibition of CLC-7.bioRxiv : the preprint server for biology · 2025Article
- Parkinson Disease Signaling Pathways, Molecular Mechanisms, and Potential Therapeutic Strategies: A Comprehensive Review.International journal of molecular sciences · 2025Review
- The polyamine transporter ATP13A3 mediates difluoromethylornithine-induced polyamine uptake in neuroblastoma.Molecular oncology · 2025Article
- Spastic Paraplegia Type 78 Associated With ATP13A2 Gene Variants in Compound Heterozygosity.Molecular genetics & genomic medicine · 2025Article
- Substrates, regulation, cellular functions, and disease associations of P4-ATPases.Communications biology · 2025Review
- The structure and function of P5A-ATPases.Nature communications · 2024Article
- Lysosomal dysfunction in α-synuclein pathology: molecular mechanisms and therapeutic strategies.Cellular and molecular life sciences : CMLS · 2024Review
- A novel ATP13A2 variant causing complicated hereditary spastic paraplegia.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2024Article
- Parkinson's disease-associated ATP13A2/PARK9 functions as a lysosomal HNature communications · 2023Article
- Conformational cycle of human polyamine transporter ATP13A2.Nature communications · 2023Article
- Signaling pathways in Parkinson's disease: molecular mechanisms and therapeutic interventions.Signal transduction and targeted therapy · 2023Review
- ATP13A2 (PARK9) and basal ganglia function.Frontiers in neurology · 2023Review
- Article
- ATP13A2 protects dopaminergic neurons in Parkinson's disease: from biology to pathology.Journal of biomedical research · 2022Article
- ATP13A3 facilitates polyamine transport in human pancreatic cancer cells.Scientific reports · 2022Article
- Mitochondrial Dysfunction in Parkinson's Disease: From Mechanistic Insights to Therapy.Frontiers in aging neuroscience · 2022Review
- Cryo-EM reveals mechanistic insights into lipid-facilitated polyamine export by human ATP13A2.Molecular cell · 2021Article
- Structural basis of polyamine transport by human ATP13A2 (PARK9).Molecular cell · 2021Article
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Authors and funding
14 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
ATP13A2 is a lysosomal P-type transport ATPase that has been implicated in Kufor-Rakeb syndrome and Parkinson's disease (PD), providing protection against α-synuclein, Mn(2+), and Zn(2+) toxicity in various model systems. So far, the molecular function and regulation of ATP13A2 remains undetermined. Here, we demonstrate that ATP13A2 contains a unique N-terminal hydrophobic extension that lies on the cytosolic membrane surface of the lysosome, where it interacts with the lysosomal signaling lipids phosphatidic acid (PA) and phosphatidylinositol(3,5)bisphosphate [PI(3,5)P2]. We further demonstrate that ATP13A2 accumulates in an inactive autophosphorylated state and that PA and PI(3,5)P2 stimulate the autophosphorylation of ATP13A2. In a cellular model of PD, only catalytically active ATP13A2 offers cellular protection against rotenone-induced mitochondrial stress, which relies on the availability of PA and PI(3,5)P2. Thus, the N-terminal binding of PA and PI(3,5)P2 emerges as a key to unlock the activity of ATP13A2, which may offer a therapeutic strategy to activate ATP13A2 and thereby reduce α-synuclein toxicity or mitochondrial stress in PD or related disorders.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.