The Ca super(2+)/Mn super(2+) ion-pump PMR1 links elevation of cytosolic Ca super(2+) levels to alpha -synuclein toxicity in Parkinson's disease models

• Published in: Cell death and differentiation Vol. 20; no. 3; pp. 465 - 477
• Main Authors: Buettner, S, Faes, L, Reichelt, W N, 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, T R, Freudenberger, P, Kroemer, G, Sigrist, S J, Winderickx, J, Callewaert, G, Tavernarakis, N, Madeo, F
• Format: Journal Article
• Language: English
• Published: 01.03.2013
• Subjects: Nematoda
• ISSN: 1350-9047
• DOI: 10.1038/cdd.2012.142

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 Ca super(2+) fluxes, arguing for an involvement of deregulated Ca super(2+) homeostasis in this neuronal demise. Here, we identify the Golgi-resident Ca super(2+)/Mn super(2+) ATPase PMR1 (plasma membrane-related Ca super(2+)-ATPase 1) as a phylogenetically conserved mediator of alpha Syn-driven changes in Ca super(2+) homeostasis and cytotoxicity. Expression of alpha Syn in yeast resulted in elevated cytosolic Ca super(2+) 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 Ca super(2+) levels is pivotal for its cytotoxicity and requires PMR1.