ATP13A2 deficiency disrupts lysosomal polyamine export

Veen, Sarah van; Martin, Shaun; Haute, Chris van den; Benoy, Veronick; Lyons, Joseph; Vanhoutte, Roeland; Kahler, Jan Pascal; Decuypere, Jean-Paul; Gelders, Geraldine; Lambie, Eric; Zielich, Jeffrey; Swinnen, Johannes V.; Annaert, Wim; Agostinis, Patrizia; Ghesquiere, Bart; Verhelst, Steven; Baekelandt, Veerle; Eggermont, Jan und Vangheluwe, Peter (2020): ATP13A2 deficiency disrupts lysosomal polyamine export. In: Nature, Bd. 578, Nr. 7795: S. 419-424

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 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. The lysosomal polyamine transporter ATP13A2 controls the cellular polyamine content, and impaired lysosomal polyamine export represents a lysosome-dependent cell death pathway that may be implicated in ATP13A2-associated neurodegeneration.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Biologie > Department Biologie II
• Themengebiete: 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften; Biologie
• ISSN: 0028-0836
• Sprache: Englisch