The Ca2+/Mn2+ ion-pump PMR1 links elevation of cytosolic Ca2+ levels to α-synuclein toxicity in Parkinson's disease models

被引：55

作者：

Buettner, S. ^{[1
]}

Faes, L. ^{[2
,3
]}

Reichelt, W. N. ^{[1
]}

Broeskamp, F. ^{[1
]}

Habernig, L. ^{[1
]}

Benke, S. ^{[1
]}

Kourtis, N. ^{[4
]}

Ruli, D. ^{[1
]}

Carmona-Gutierrez, D. ^{[1
]}

Eisenberg, T. ^{[1
]}

D'hooge, P. ^{[2
]}

Ghillebert, R. ^{[3
]}

Franssens, V. ^{[3
]}

Harger, A. ^{[5
]}

Pieber, T. R. ^{[5
]}

Freudenberger, P. ^{[1
]}

Kroemer, G. ^{[6
,7
,8
,9
,10
]}

Sigrist, S. J. ^{[11
]}

Winderickx, J. ^{[3
]}

Callewaert, G. ^{[2
]}

Tavernarakis, N. ^{[4
]}

Madeo, F. ^{[1
]}

机构：

[1] Graz Univ, Inst Mol Biosci, Graz, Austria

[2] Katholieke Univ Leuven, Res Grp Neurodegenerat, Kortrijk, Belgium

[3] Katholieke Univ Leuven, Louvain, Belgium

[4] Fdn Res & Technol Hellas, Inst Mol Biol & Biotechnol, Iraklion, Greece

[5] Med Univ Graz, Dept Internal Med, Graz, Austria

[6] Inst Gustave Roussy, INSERM, U848, F-94805 Villejuif, France

[7] Inst Gustave Roussy, Villejuif, France

[8] Ctr Rech Cordeliers, Paris, France

[9] Hop Europeen Georges Pompidou, AP HP, Paris, France

[10] Univ Paris 05, Sorbonne Paris Cite, Paris, France

[11] Free Univ Berlin, Inst Biol Genet, Berlin, Germany

来源：

CELL DEATH AND DIFFERENTIATION | 2013年 / 20卷 / 03期

基金：

奥地利科学基金会; 欧洲研究理事会;

关键词：

Parkinson's disease models; alpha-synuclein; Ca2+ homeostasis; yeast cell death; PMR1; dopaminergic neuron loss; YEAST SECRETORY PATHWAY; FUNCTIONAL EXPRESSION; OXIDATIVE STRESS; CALCIUM; HOMEOSTASIS; APOPTOSIS; MUTATION; MITOCHONDRIA; INHIBITION; TRANSPORT;

D O I：

10.1038/cdd.2012.142

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons, which arises from a yet elusive concurrence between genetic and environmental factors. The protein alpha-synuclein (alpha Syn), the principle toxic effector in PD, has been shown to interfere with neuronal Ca2+ fluxes, arguing for an involvement of deregulated Ca2+ homeostasis in this neuronal demise. Here, we identify the Golgi-resident Ca2+/Mn2+ ATPase PMR1 (plasma membrane-related Ca2+-ATPase 1) as a phylogenetically conserved mediator of alpha Syn-driven changes in Ca2+ homeostasis and cytotoxicity. Expression of alpha Syn in yeast resulted in elevated cytosolic Ca2+ levels and increased cell death, both of which could be inhibited by deletion of PMR1. Accordingly, absence of PMR1 prevented alpha Syn-induced loss of dopaminergic neurons in nematodes and flies. In addition, alpha Syn failed to compromise locomotion and survival of flies when PMR1 was absent. In conclusion, the alpha Syn-driven rise of cytosolic Ca2+ levels is pivotal for its cytotoxicity and requires PMR1. Cell Death and Differentiation (2013) 20, 465-477; doi:10.1038/cdd.2012.142; published online 16 November 2012

引用

页码：465 / 477

页数：13

共 61 条

[1] Expanding insights of mitochondrial dysfunction in Parkinson's disease [J].