Buttner S et al. (2013) Cell Death Differ "The Ca2+/Mn2+ ion-pump PMR1 links elevation of cytosolic Ca(2+) levels to -synuclein toxicity in Parkinson's disease models."

Freudenberger P, Sigrist SJ, Ruli D, Habernig L, Faes L, Eisenberg T, Tavernarakis N, Reichelt WN, Kroemer G, Ghillebert R, Broeskamp F, Kourtis N, Callewaert G, Harger A, Winderickx J, Carmona-Gutierrez D, Madeo F, Franssens V, Pieber TR, D'hooge P, Buttner S, Benke S

[Cell Death Differ, 2013]

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 -synuclein (Syn), 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 Syn-driven changes in Ca(2+) homeostasis and cytotoxicity. Expression of Syn 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 Syn-induced loss of dopaminergic neurons in nematodes and flies. In addition, Syn failed to compromise locomotion and survival of flies when PMR1 was absent. In conclusion, the Syn-driven rise of cytosolic Ca(2+) levels is pivotal for its cytotoxicity and requires PMR1.