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- Title
The Ca<sup>2+</sup>/Mn<sup>2+</sup> ion-pump PMR1 links elevation of cytosolic Ca<sup>2+</sup> levels to α-synuclein toxicity in Parkinson's disease models.
- Authors
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; Callewaert, G
- 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 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.
- Publication
Cell Death & Differentiation, 2013, Vol 20, Issue 3, p465
- ISSN
1350-9047
- Publication type
Academic Journal
- DOI
10.1038/cdd.2012.142