ATP13A2 deficiency disrupts lysosomal polyamine export.

Autor: van Veen S; Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium., Martin S; Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium., Van den Haute C; Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, Leuven, Belgium.; Leuven Viral Vector Core, KU Leuven, Leuven, Belgium., Benoy V; Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium., Lyons J; Department of Molecular Biology and Genetics - DANDRITE, Aarhus, Denmark., Vanhoutte R; Laboratory of Chemical Biology, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium., Kahler JP; Laboratory of Chemical Biology, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium., Decuypere JP; Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.; Laboratory of Lipid Metabolism and Cancer, Department of Oncology, LKI - Leuven Cancer Institute, KU Leuven, Leuven, Belgium.; Laboratory of Membrane Trafficking (VIB-KU Leuven Center for Brain and Disease Research), Department of Neurosciences, KU Leuven, Leuven, Belgium.; Laboratory of Cell Death Research and Therapy, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium., Gelders G; Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, Leuven, Belgium., Lambie E; Cell and Developmental Biology, Department Biology II, Ludwig-Maximilians-Universität Munich, Munich, Germany.; Department of Cell and Developmental Biology, University College London, London, UK., Zielich J; Cell and Developmental Biology, Department Biology II, Ludwig-Maximilians-Universität Munich, Munich, Germany., Swinnen JV; Laboratory of Lipid Metabolism and Cancer, Department of Oncology, LKI - Leuven Cancer Institute, KU Leuven, Leuven, Belgium., Annaert W; Laboratory of Membrane Trafficking (VIB-KU Leuven Center for Brain and Disease Research), Department of Neurosciences, KU Leuven, Leuven, Belgium., Agostinis P; Laboratory of Cell Death Research and Therapy, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.; VIB-KU Leuven Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium., Ghesquière B; Metabolomics Expertise Center (VIB-KU Leuven Center for Cancer Biology), Department of Oncology, KU Leuven, Leuven, Belgium., Verhelst S; Laboratory of Chemical Biology, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.; Leibniz Institute for Analytical Sciences ISAS, Dortmund, Germany., Baekelandt V; Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, Leuven, Belgium., Eggermont J; Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium., Vangheluwe P; Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium. peter.vangheluwe@kuleuven.be.
Jazyk: angličtina
Zdroj: Nature [Nature] 2020 Feb; Vol. 578 (7795), pp. 419-424. Date of Electronic Publication: 2020 Jan 29.
DOI: 10.1038/s41586-020-1968-7
Abstrakt: ATP13A2 (PARK9) is a late endolysosomal transporter that is genetically implicated in a spectrum of neurodegenerative disorders, including Kufor-Rakeb syndrome-a parkinsonism with dementia 1 -and early-onset Parkinson's disease 2 . ATP13A2 offers protection against genetic and environmental risk factors of Parkinson's disease, whereas loss of ATP13A2 compromises lysosomes 3 . However, the transport function of ATP13A2 in lysosomes remains unclear. Here we establish ATP13A2 as a lysosomal polyamine exporter that shows the highest affinity for spermine among the polyamines examined. Polyamines stimulate the activity of purified ATP13A2, whereas ATP13A2 mutants that are implicated in disease are functionally impaired to a degree that correlates with the disease phenotype. ATP13A2 promotes the cellular uptake of polyamines by endocytosis and transports them into the cytosol, highlighting a role for endolysosomes in the uptake of polyamines into cells. At high concentrations polyamines induce cell toxicity, which is exacerbated by ATP13A2 loss due to lysosomal dysfunction, lysosomal rupture and cathepsin B activation. This phenotype is recapitulated in neurons and nematodes with impaired expression of ATP13A2 or its orthologues. We present defective lysosomal polyamine export as a mechanism for lysosome-dependent cell death that may be implicated in neurodegeneration, and shed light on the molecular identity of the mammalian polyamine transport system.
Databáze: MEDLINE
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