ATP13A2 deficiency disrupts lysosomal polyamine export

Sarah Veen, Shaun Martin, Chris Van den Haute, Veronick Benoy, Joseph Lyons, Roeland Vanhoutte, Jan Pascal Kahler, Jean-Paul Decuypere, Géraldine Gelders, Eric Lambie, Jeffrey Zielich, Johannes V. Swinnen, Wim Annaert, Patrizia Agostinis, Bart Ghesquière, Steven Verhelst, Veerle Baekelandt, Jan Eggermont and Peter Vangheluwe ()
Additional contact information
Sarah Veen: KU Leuven
Shaun Martin: KU Leuven
Chris Van den Haute: KU Leuven
Veronick Benoy: KU Leuven
Joseph Lyons: Department of Molecular Biology and Genetics – DANDRITE
Roeland Vanhoutte: KU Leuven
Jan Pascal Kahler: KU Leuven
Jean-Paul Decuypere: KU Leuven
Géraldine Gelders: KU Leuven
Eric Lambie: Ludwig-Maximilians-Universität Munich
Jeffrey Zielich: Ludwig-Maximilians-Universität Munich
Johannes V. Swinnen: LKI – Leuven Cancer Institute, KU Leuven
Wim Annaert: KU Leuven
Patrizia Agostinis: KU Leuven
Bart Ghesquière: KU Leuven
Steven Verhelst: KU Leuven
Veerle Baekelandt: KU Leuven
Jan Eggermont: KU Leuven
Peter Vangheluwe: KU Leuven

Nature, 2020, vol. 578, issue 7795, 419-424

Abstract: Abstract ATP13A2 (PARK9) is a late endolysosomal transporter that is genetically implicated in a spectrum of neurodegenerative disorders, including Kufor-Rakeb syndrome—a parkinsonism with dementia1—and early-onset Parkinson’s disease2. ATP13A2 offers protection against genetic and environmental risk factors of Parkinson’s disease, whereas loss of ATP13A2 compromises lysosomes3. 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.

Date: 2020
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DOI: 10.1038/s41586-020-1968-7

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