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α-突触核蛋白聚集激活钙泵 SERCA，导致钙稳态失衡。

Alpha-synuclein aggregates activate calcium pump SERCA leading to calcium dysregulation.

机构信息

Danish Research Institute of Translational Neuroscience - DANDRITE, Aarhus University, Aarhus, Denmark.

Department of Biomedicine, Aarhus University, Aarhus, Denmark.

出版信息

EMBO Rep. 2018 May;19(5). doi: 10.15252/embr.201744617. Epub 2018 Mar 29.

DOI:10.15252/embr.201744617
PMID:29599149
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5934765/
Abstract

Aggregation of α-synuclein is a hallmark of Parkinson's disease and dementia with Lewy bodies. We here investigate the relationship between cytosolic Ca and α-synuclein aggregation. Analyses of cell lines and primary culture models of α-synuclein cytopathology reveal an early phase with reduced cytosolic Ca levels followed by a later Ca increase. Aggregated but not monomeric α-synuclein binds to and activates SERCA , and proximity ligation assays confirm this interaction in cells. The SERCA inhibitor cyclopiazonic acid (CPA) normalises both the initial reduction and the later increase in cytosolic Ca CPA protects the cells against α-synuclein-aggregate stress and improves viability in cell models and in Proximity ligation assays also reveal an increased interaction between α-synuclein aggregates and SERCA in human brains affected by dementia with Lewy bodies. We conclude that α-synuclein aggregates bind SERCA and stimulate its activity. Reducing SERCA activity is neuroprotective, indicating that SERCA and down-stream processes may be therapeutic targets for treating α-synucleinopathies.

摘要

α-突触核蛋白的聚集是帕金森病和路易体痴呆的标志。我们在这里研究细胞浆钙离子与α-突触核蛋白聚集之间的关系。对α-突触核蛋白细胞病变的细胞系和原代培养模型的分析显示，早期细胞浆钙离子水平降低，随后钙离子增加。聚集的但不是单体的α-突触核蛋白与 SERCA 结合并激活 SERCA，并且接近连接测定证实了细胞中的这种相互作用。SERCA 抑制剂环匹阿尼酸（CPA）使细胞浆钙离子的初始减少和随后的增加正常化，CPA 保护细胞免受α-突触核蛋白聚集应激，并改善细胞模型中的活力。接近连接测定还揭示了在受路易体痴呆影响的人类大脑中，α-突触核蛋白聚集体与 SERCA 之间的相互作用增加。我们得出结论，α-突触核蛋白聚集体与 SERCA 结合并刺激其活性。降低 SERCA 活性具有神经保护作用，表明 SERCA 和下游过程可能是治疗α-突触核蛋白病的治疗靶点。

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