钙/钙调蛋白依赖性丝氨酸蛋白激酶通过磷酸化帕金森病中的α-突触核蛋白加剧线粒体钙单向转运体相关的线粒体钙超载。
Calcium/calmodulin-dependent serine protein kinase exacerbates mitochondrial calcium uniporter-related mitochondrial calcium overload by phosphorylating α-synuclein in Parkinson's disease.
作者信息
Zhang Qingxi, Huang Yin, Wu Anbiao, Duan Qingrui, He Peikun, Huang Haifeng, Gao Yuyuan, Nie Kun, Liu Qicai, Wang Lijuan
机构信息
Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510100, China; Department of Neurology, Guangdong Neuroscience Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China; Guangzhou Key Laboratory of Diagnosis and Treatment for Neurodegenerative Diseases, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China.
The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China.
出版信息
Int J Biochem Cell Biol. 2023 Apr;157:106385. doi: 10.1016/j.biocel.2023.106385. Epub 2023 Feb 7.
α-Synuclein phosphorylation and mitochondrial calcium homeostasis are important mechanisms underlying mitochondrial dysfunction in Parkinson's disease, but the network regulating these mechanisms remains unclear. We identified the role of key phosphokinases and the pathological effects of α-synuclein phosphorylation on mitochondrial calcium influx and mitochondrial function in Parkinson's disease. The function of the key phosphokinase, calcium/calmodulin-dependent serine protein kinase, was investigated through loss- and gain-of-function experiments using a cell model of Parkinson's disease. The regulation of mitochondrial calcium uniporter-mediated mitochondrial calcium influx by calcium/calmodulin-dependent serine protein kinase was explored using a cellular model of Parkinson's disease. Coimmunoprecipitation experiments and α-synuclein mutation were used to explore the mechanism through which calcium/calmodulin-dependent serine protein kinase regulates mitochondrial calcium uniporter-mediated mitochondrial calcium influx and exacerbates mitochondrial damage in Parkinson's disease. Here, we show the pathogenic role of calcium/calmodulin-dependent serine protein kinase in Parkinson's disease progression. Calcium/calmodulin-dependent serine protein kinase phosphorylated α-synuclein to activate mitochondrial calcium uniporter and thus increase mitochondrial calcium influx, and these effects were blocked by α-synuclein S129A mutant expression. Furthermore, the calcium/calmodulin-dependent serine protein kinase inhibitor CASK-IN-1 exerted neuroprotective effects in Parkinson's disease. Collectively, our results suggest that calcium/calmodulin-dependent serine protein kinase phosphorylates α-synuclein to activate the mitochondrial calcium uniporter and thereby causes mitochondrial calcium overload and mitochondrial damage in Parkinson's disease. We elucidated a new role of calcium/calmodulin-dependent serine protein kinase in Parkinson's disease and revealed the potential therapeutic value of targeting calcium/calmodulin-dependent serine protein kinase in Parkinson's disease treatment.
α-突触核蛋白磷酸化和线粒体钙稳态是帕金森病中线粒体功能障碍的重要潜在机制，但调节这些机制的网络仍不清楚。我们确定了关键磷酸激酶的作用以及α-突触核蛋白磷酸化对帕金森病中线粒体钙内流和线粒体功能的病理影响。通过使用帕金森病细胞模型进行功能丧失和功能获得实验，研究了关键磷酸激酶钙/钙调蛋白依赖性丝氨酸蛋白激酶的功能。利用帕金森病细胞模型探讨了钙/钙调蛋白依赖性丝氨酸蛋白激酶对线粒体钙单向转运体介导的线粒体钙内流的调节作用。采用免疫共沉淀实验和α-突触核蛋白突变来探索钙/钙调蛋白依赖性丝氨酸蛋白激酶调节线粒体钙单向转运体介导的线粒体钙内流并加重帕金森病中线粒体损伤的机制。在此，我们展示了钙/钙调蛋白依赖性丝氨酸蛋白激酶在帕金森病进展中的致病作用。钙/钙调蛋白依赖性丝氨酸蛋白激酶使α-突触核蛋白磷酸化以激活线粒体钙单向转运体，从而增加线粒体钙内流，而这些作用被α-突触核蛋白S129A突变体表达所阻断。此外，钙/钙调蛋白依赖性丝氨酸蛋白激酶抑制剂CASK-IN-1在帕金森病中发挥神经保护作用。总的来说，我们的结果表明，钙/钙调蛋白依赖性丝氨酸蛋白激酶使α-突触核蛋白磷酸化以激活线粒体钙单向转运体，从而导致帕金森病中的线粒体钙超载和线粒体损伤。我们阐明了钙/钙调蛋白依赖性丝氨酸蛋白激酶在帕金森病中的新作用，并揭示了靶向钙/钙调蛋白依赖性丝氨酸蛋白激酶在帕金森病治疗中的潜在治疗价值。
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