Institute of Molecular Biosciences; University of Graz, Humboldtstrasse 50/EG, Graz, Austria.
Cell Death Differ. 2013 Mar;20(3):465-77. doi: 10.1038/cdd.2012.142. Epub 2012 Nov 16.
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.
帕金森病（PD）的特征是多巴胺能神经元进行性丧失，这是遗传和环境因素之间尚未明确的共同作用所致。α-突触核蛋白（αSyn）是 PD 中的主要毒性效应物，已被证明会干扰神经元 Ca(2+)流，这表明 Ca(2+)稳态失调参与了这种神经元死亡。在这里，我们确定驻留在高尔基体的 Ca(2+)/Mn(2+)ATP 酶 PMR1（质膜相关的 Ca(2+)-ATP 酶 1）是 αSyn 驱动的 Ca(2+)稳态和细胞毒性变化的保守介质。αSyn 在酵母中的表达导致细胞内 Ca(2+)水平升高和细胞死亡增加，这两者都可以通过 PMR1 的缺失来抑制。因此，当 PMR1 缺失时，αSyn 诱导的多巴胺能神经元丧失在线虫和果蝇中被阻止。此外，当 PMR1 缺失时，αSyn 无法损害果蝇的运动和存活。总之，αSyn 驱动的细胞内 Ca(2+)水平升高对其细胞毒性至关重要，并且需要 PMR1。
