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Selected Publication:
SHR Neuro Cancer Cardio Lipid Metab Microb
Büttner, S; Faes, L; Reichelt, WN; 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, TR; Freudenberger, P; Kroemer, G; Sigrist, SJ; Winderickx, J; Callewaert, G; Tavernarakis, N; Madeo, F.
The Ca2+/Mn2+ ion-pump PMR1 links elevation of cytosolic Ca(2+) levels to α-synuclein toxicity in Parkinson's disease models.
Cell Death Differ. 2013; 20(3):465-477
Doi: 10.1038/cdd.2012.142
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- Co-authors Med Uni Graz
- Freudenberger Paul
- Harger Alexandra
- Pieber Thomas
- Ruli Doris
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- 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 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 αSyn-driven changes in Ca(2+) homeostasis and cytotoxicity. Expression of αSyn 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 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 Ca(2+) levels is pivotal for its cytotoxicity and requires PMR1.
- Find related publications in this database (using NLM MeSH Indexing)
- Acetylcysteine - pharmacology
- Animals -
- Apoptosis -
- Caenorhabditis elegans - metabolism
- Caenorhabditis elegans Proteins - genetics
- Calcium - metabolism
- Calcium-Transporting ATPases - deficiency
- Humans -
- Manganese - metabolism
- Models, Biological -
- Oxidative Stress -
- Parkinson Disease - metabolism
- Phosphorylation -
- Promoter Regions, Genetic -
- RNA Interference -
- RNA, Small Interfering - metabolism
- Saccharomyces cerevisiae - drug effects
- Saccharomyces cerevisiae Proteins - genetics
- alpha-Synuclein - genetics
- Find related publications in this database (Keywords)
- Parkinson's disease models
- alpha-synuclein
- Ca2+ homeostasis
- yeast cell death
- PMR1
- dopaminergic neuron loss