1. The Ca2+/Mn2+ ion-pump PMR1 links elevation of cytosolic Ca2+ levels to α-synuclein toxicity in Parkinson's disease models.
- Author
-
Büttner, 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, and Callewaert, G
- Subjects
PARKINSON'S disease ,DOPAMINERGIC neurons ,SYNUCLEINS ,GENE expression ,DOPAMINERGIC mechanisms ,PHYSIOLOGICAL control systems ,EDIBLE fungi - 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 α-synuclein (αSyn), the principle toxic effector in PD, has been shown to interfere with neuronal Ca
2+ 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]- Published
- 2013
- Full Text
- View/download PDF