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Title: The Ca2+/Mn2+ ion-pump Pmr1 links elevation of cytosolic Ca2+ levels to a-synuclein toxicity in Parkinson's disease models
Authors: Buttner, Sabrina *
Faes, Liesbeth *
Wieland, Reichelt *
Broeskamp, Filomena
Habernig, Lukas
Stefan, Benke
Nektarios, Student
Sigrist, Stephan J
Ruli, Doris
D'hooge, Petra
Ghillebert, Ruben
Eisenberg, Tobias
Carmona-Gutierrez, Didac
Hollmann, Christina
Franssens, Vanessa
Harger, Alexandra
Pieber, Thomas R
Freudenberger, Paul
Kroemer, Guido
Winderickx, Joris
Callewaert, Geert ×
Tavernarakis, Nektarios
Madeo, Frank #
Issue Date: Mar-2013
Publisher: E. Arnold
Series Title: Cell Death and Differentiation vol:20 issue:3 pages:465-477
Article number: 10.1038/cdd.2012.142
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.
URI: 
ISSN: 1350-9047
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Molecular Physiology of Plants and Micro-organisms Section - miscellaneous
Laboratory for Functional Biology (-)
Faculty of Medicine, Campus Kulak Kortrijk
Physiology, Kulak (-)
* (joint) first author
× corresponding author
# (joint) last author

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