title: The Ca2+/Mn2+ ion-pump PMR1 links elevation of cytosolic Ca(2+) levels to α-synuclein toxicity in Parkinson's disease models.
abstract: 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 α-synuclein (αSyn), the principle toxic effector in PD, has been shown to interfere with neuronal Ca(2+) fluxes, arguing for an involvement of deregulated Ca(2+) homeostasis in this neuronal demise. Here, we identify the Golgi-resident Ca(2+)/Mn(2+) ATPase PMR1 (plasma membrane-related Ca(2+)-ATPase 1) as a phylogenetically conserved mediator of αSyn-driven changes in Ca(2+) homeostasis and cytotoxicity. Expression of αSyn in yeast resulted in elevated cytosolic Ca(2+) levels and increased cell death, both of which could be inhibited by deletion of PMR1. Accordingly, absence of PMR1 prevented αSyn-induced loss of dopaminergic neurons in nematodes and flies. In addition, αSyn failed to compromise locomotion and survival of flies when PMR1 was absent. In conclusion, the αSyn-driven rise of cytosolic Ca(2+) levels is pivotal for its cytotoxicity and requires PMR1.
authors.affiliation: Institute of Molecular Biosciences; University of Graz, Humboldtstrasse 50/EG, Graz, Austria.
authors.forename: S
authors.initials: S
authors.lastname: Büttner
authors.forename: L
authors.initials: L
authors.lastname: Faes
authors.forename: W N
authors.initials: WN
authors.lastname: Reichelt
authors.forename: F
authors.initials: F
authors.lastname: Broeskamp
authors.forename: L
authors.initials: L
authors.lastname: Habernig
authors.forename: S
authors.initials: S
authors.lastname: Benke
authors.forename: N
authors.initials: N
authors.lastname: Kourtis
authors.forename: D
authors.initials: D
authors.lastname: Ruli
authors.forename: D
authors.initials: D
authors.lastname: Carmona-Gutierrez
authors.forename: T
authors.initials: T
authors.lastname: Eisenberg
authors.forename: P
authors.initials: P
authors.lastname: D'hooge
authors.forename: R
authors.initials: R
authors.lastname: Ghillebert
authors.forename: V
authors.initials: V
authors.lastname: Franssens
authors.forename: A
authors.initials: A
authors.lastname: Harger
authors.forename: T R
authors.initials: TR
authors.lastname: Pieber
authors.forename: P
authors.initials: P
authors.lastname: Freudenberger
authors.forename: G
authors.initials: G
authors.lastname: Kroemer
authors.forename: S J
authors.initials: SJ
authors.lastname: Sigrist
authors.forename: J
authors.initials: J
authors.lastname: Winderickx
authors.forename: G
authors.initials: G
authors.lastname: Callewaert
authors.forename: N
authors.initials: N
authors.lastname: Tavernarakis
authors.forename: F
authors.initials: F
authors.lastname: Madeo
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D017173:Caenorhabditis elegans / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008345:Manganese / Q000378:metabolism; D008954:Models, Biological; D018832:Molecular Chaperones; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity
chemical_list: D029742:Caenorhabditis elegans Proteins; D018832:Molecular Chaperones; D034741:RNA, Small Interfering; C101767:SSC1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D051844:alpha-Synuclein; C499334:pmr-1 protein, C elegans; D008345:Manganese; D000252:Calcium-Transporting ATPases; D002118:Calcium; D000111:Acetylcysteine