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TP13A2的缺失破坏溶酶体多胺的输出
2020-02-10 09:47

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。

研究人员将ATP13A2鉴定为为溶酶体多胺输出蛋白,它在所测试的多胺中显示出对精胺有最高亲和力。多胺激活纯化的ATP13A2活性,而与疾病有关的ATP13A2突变体在功能上受损的程度与疾病表型相关。ATP13A2通过内吞作用促进细胞吸收多胺并将其转运到细胞质中,从而突出了溶酶体在多胺吸收到细胞中的作用。在高浓度下,多胺会诱导细胞毒性,而ATP13A2的缺失则加剧这种毒性,这由溶酶体功能障碍、溶酶体破裂和组织蛋白酶B活化所导致。该表型在具有ATP13A2或其直系同源物表达受损的神经元和线虫中得以重现。研究人员认为失调的溶酶体多胺输出蛋白可能是影响神经退行性的溶酶体依赖性细胞死亡的机制,并阐明了哺乳动物多胺转运系统的分子身份。
 
据了解,ATP13A2(PARK9)是一种晚期溶酶体转运蛋白,与多种神经退行性疾病有遗传相关性,包括Kufor-Rakeb综合征(一种患有痴呆症的帕金森病)和早发性帕金森氏病。ATP13A2可以抵抗帕金森氏病的遗传和环境危险因素,而ATP13A2的丢失会损害溶酶体。但是,尚不清楚ATP13A2在溶酶体中的转运功能。
 
附:英文原文
 
Title: ATP13A2 deficiency disrupts lysosomal polyamine export

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


本期文章:《自然》:Online/在线发表

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