1. The Ca2+/Mn2+ ion-pump PMR1 links elevation of cytosolic Ca(2+) levels to α-synuclein toxicity in Parkinson's disease models.
- Author
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Büttner S, Faes L, Reichelt WN, Broeskamp F, Habernig L, Benke S, Kourtis N, Ruli D, Carmona-Gutierrez D, Eisenberg T, D'hooge P, Ghillebert R, Franssens V, Harger A, Pieber TR, Freudenberger P, Kroemer G, Sigrist SJ, Winderickx J, Callewaert G, Tavernarakis N, and Madeo F
- Subjects
- Acetylcysteine pharmacology, Animals, Apoptosis, Caenorhabditis elegans metabolism, Caenorhabditis elegans Proteins genetics, Caenorhabditis elegans Proteins metabolism, Calcium-Transporting ATPases deficiency, Calcium-Transporting ATPases genetics, Humans, Manganese metabolism, Molecular Chaperones, Oxidative Stress, Parkinson Disease metabolism, Parkinson Disease pathology, Phosphorylation, Promoter Regions, Genetic, RNA Interference, RNA, Small Interfering metabolism, Saccharomyces cerevisiae drug effects, Saccharomyces cerevisiae metabolism, Saccharomyces cerevisiae Proteins genetics, alpha-Synuclein genetics, alpha-Synuclein toxicity, Calcium metabolism, Calcium-Transporting ATPases metabolism, Models, Biological, Saccharomyces cerevisiae Proteins metabolism, alpha-Synuclein metabolism
- 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.
- Published
- 2013
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