ATP13A2 deficiency disrupts lysosomal polyamine export

doi:10.1038/s41586-020-1968-7

GSTDTAP > 地球科学

DOI	10.1038/s41586-020-1968-7
	ATP13A2 deficiency disrupts lysosomal polyamine export
	Nienhuis, J. H.3,4; Ashton, A. D.5; Edmonds, D. A.6; Hoitink, A. J. F.3; Kettner, A. J.7; Rowland, J. C.8; Tornqvist, T. E.4
	2020
发表期刊	NATURE
ISSN	0028-0836
EISSN	1476-4687
出版年	2020
卷号	578 期号:7795 页码:419-+
文章类型	Article
语种	英语
国家	Belgium; Denmark; Germany; England
英文关键词	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.
领域	地球科学 ; 气候变化 ; 资源环境
收录类别	SCI-E
WOS记录号	WOS:000510138600008
WOS关键词	ALPHA-SYNUCLEIN ; PARKINSON DISEASE ; PROTEIN ; EXPRESSION ; MUTATIONS ; INTEGRATION ; VARIANT ; VECTORS ; LEADS ; YEAST
WOS类目	Multidisciplinary Sciences
WOS研究方向	Science & Technology - Other Topics
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/281322
专题	地球科学资源环境科学气候变化
作者单位	1.Univ Utrecht, Dept Phys Geog, Utrecht, Netherlands; 2.Florida State Univ, Dept Earth Ocean & Atmospher Sci, Tallahassee, FL 32306 USA; 3.Wageningen Univ & Res, Environm Sci, Wageningen, Netherlands; 4.Tulane Univ, Dept Earth & Environm Sci, New Orleans, LA 70118 USA; 5.Woods Hole Oceanog Inst, Dept Geol & Geophys, Woods Hole, MA 02543 USA; 6.Indiana Univ, Dept Earth & Atmospher Sci, Bloomington, IN USA; 7.Univ Colorado, Inst Arctic & Alpine Res, Boulder, CO 80309 USA; 8.Los Alamos Natl Lab, Earth & Environm Sci Div, Los Alamos, NM USA
推荐引用方式 GB/T 7714	Nienhuis, J. H.,Ashton, A. D.,Edmonds, D. A.,et al. ATP13A2 deficiency disrupts lysosomal polyamine export[J]. NATURE,2020,578(7795):419-+.
APA	Nienhuis, J. H..,Ashton, A. D..,Edmonds, D. A..,Hoitink, A. J. F..,Kettner, A. J..,...&Tornqvist, T. E..(2020).ATP13A2 deficiency disrupts lysosomal polyamine export.NATURE,578(7795),419-+.
MLA	Nienhuis, J. H.,et al."ATP13A2 deficiency disrupts lysosomal polyamine export".NATURE 578.7795(2020):419-+.