Impairment of PARK14-dependent Ca(2+) signalling is a novel determinant of Parkinson's disease.
Impairment of PARK14-dependent Ca(2+) signalling is a novel determinant of Parkinson's disease.
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DOI：
10.1038/ncomms10332
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发表时间：
2016-01-12
影响因子：
16.6
通讯作者：
Bolotina VM
中科院分区：
文献类型：
--
作者：
Zhou Q;Yen A;Rymarczyk G;Asai H;Trengrove C;Aziz N;Kirber MT;Mostoslavsky G;Ikezu T;Wolozin B;Bolotina VM
特发性帕金森病（idPD）的病因仍然是谜，尽管最近成功地确定基因（PARKs）的基础家族性PD。为了找到这种无法治愈的神经退行性疾病的新关键，我们专注于了解甚少的PARK 14疾病基因座（Pla 2g 6基因）和钙库操纵的Ca 2+信号通路。对来自idPD患者的细胞的分析揭示了储存操作的PLA 2g 6依赖性Ca 2+信号传导的显著缺陷，我们可以在新的B6. Cg-Pla 2g 6 Δ Ex 2-VB（PLA 2g 6 ex 2KO）小鼠模型中模拟该缺陷。在这里，我们证明PLA 2g 6依赖性Ca 2+信号传导的遗传或分子损伤是自噬功能障碍、黑质致密部多巴胺（DA）神经元进行性丧失和年龄依赖性L-DOPA敏感性运动功能障碍的触发因素。这种以前未知的病理事件序列的发现，其与idPD的关联以及我们在新型遗传小鼠模型中模拟这种病理的能力，为寻找这种毁灭性神经退行性疾病的治愈方法提供了新的机会。 PLA 2g 6调节钙库操作的Ca 2+进入，并与帕金森病有关。在这里，Zhou等人在特发性PD患者中发现了错误的PLA 2g 6依赖性Ca 2+信号传导，并表明其损伤在新的PLA 2g 6 ex 2KO小鼠模型中触发了自噬功能障碍和多巴胺能神经元的损失。
The etiology of idiopathic Parkinson's disease (idPD) remains enigmatic despite recent successes in identification of genes (PARKs) that underlie familial PD. To find new keys to this incurable neurodegenerative disorder we focused on the poorly understood PARK14 disease locus (Pla2g6 gene) and the store-operated Ca2+ signalling pathway. Analysis of the cells from idPD patients reveals a significant deficiency in store-operated PLA2g6-dependent Ca2+ signalling, which we can mimic in a novel B6.Cg-Pla2g6ΔEx2-VB (PLA2g6 ex2KO) mouse model. Here we demonstrate that genetic or molecular impairment of PLA2g6-dependent Ca2+ signalling is a trigger for autophagic dysfunction, progressive loss of dopaminergic (DA) neurons in substantia nigra pars compacta and age-dependent L-DOPA-sensitive motor dysfunction. Discovery of this previously unknown sequence of pathological events, its association with idPD and our ability to mimic this pathology in a novel genetic mouse model opens new opportunities for finding a cure for this devastating neurodegenerative disease. PLA2g6 regulates store-operated Ca2+ entry and is linked to Parkinson's disease. Here, Zhou et al find faulty PLA2g6-dependent Ca2+ signaling in idiopathic PD patients, and show that its impairment triggers autophagic dysfunction and loss of dopaminergic neurons in a new PLA2g6 ex2KO mouse model.