比利时鲁汶大学Peter Vangheluwe小组近日取得一项新成果。他们的最新工作表明,ATP13A2的缺失破坏了溶酶体多胺的输出。2020年1月29日《自然》杂志在线发表了这项成果。
Author: Sarah van Veen, Shaun Martin, Chris Van den Haute, Veronick Benoy, Joseph Lyons, Roeland Vanhoutte, Jan Pascal Kahler, Jean-Paul Decuypere, Graldine Gelders, Eric Lambie, Jeffrey Zielich, Johannes V. Swinnen, Wim Annaert, Patrizia Agostinis, Bart Ghesquire, Steven Verhelst, Veerle Baekelandt, Jan Eggermont, Peter Vangheluwe
Issue&Volume: 2020-01-29
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.
DOI: 10.1038/s41586-020-1968-7
Source: https://www.nature.com/articles/s41586-020-1968-7
Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html