The Ca2+/Mn2+ ion-pump PMR1 links elevation of cytosolic Ca2+ levels to α-synuclein toxicity in Parkinson's disease models.

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 Ca²⁺ fluxes, arguing for an involvement of deregulated Ca²⁺ homeostasis in this neuronal demise. Here, we identify the Golgi-resident Ca²⁺/Mn²⁺ ATPase PMR1 (plasma membrane-related Ca²⁺-ATPase 1) as a phylogenetically conserved mediator of αSyn-driven changes in Ca²⁺ homeostasis and cytotoxicity. Expression of αSyn in yeast resulted in elevated cytosolic Ca²⁺ 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 Ca²⁺ levels is pivotal for its cytotoxicity and requires PMR1. [ABSTRACT FROM AUTHOR]