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 alpha-synuclein (alpha Syn), 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 alpha Syn-driven changes in Ca2+ homeostasis and cytotoxicity. Expression of alpha Syn 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 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 Ca2+ levels is pivotal for its cytotoxicity and requires PMR1. Cell Death and Differentiation (2013) 20, 465-477; doi:10.1038/cdd.2012.142; published online 16 November 2012