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

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 -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. © 2013 Macmillan Publishers Limited All rights reserved.