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帕金森疾病（Parkinson’s disease，PD）是一种常见的神经退行性疾病，患者主要表现出运动障碍，包括运动迟缓、肌强直、姿势异常与静止性震颤等。
帕金森疾病（Parkinson’s disease，PD）是一种常见的神经退行性疾病，患者主要表现出运动障碍，包括运动迟缓、肌强直、姿势异常与静止性震颤等。其病理特征表现为黑质致密区多巴胺神经元丢失和路易小体的形成。目前，全球有六百多万人正遭受帕金森病的折磨，随着我国人口老龄化的加剧，PD带来的社会负担日渐沉重。MPTP是一种选择性破坏多巴胺神经元的神经毒素，其作用机制为抑制线粒体复合物I的活性，导致线粒体功能紊乱，表现为细胞内活性氧（ROS）的升高、线粒体膜电位崩溃、ATP消耗，最终导致多巴胺神经元损伤和死亡。目前，MPTP被广泛应用于构建各种PD动物模型。然而，MPTP导致多巴胺神经元损伤的具体分子机制和信号途径还有待阐明。
自噬是一种细胞自身降解细胞器和错误折叠蛋白的过程。大量研究表明，线粒体自噬在PD的发生发展中发挥重要的作用，但自噬在PD疾病中的具体作用机制还不清楚。为了阐明自噬在PD过程中承担的作用，寻找潜在的早期干预措施，中国科学院昆明动物研究所博士研究生苏凌燕、李浩和硕士研究生吕莉等在研究员姚永刚与胡新天的指导下，从分子、细胞、啮齿类动物模型和猕猴动物模型等多个层次开展了系统的研究。研究结果显示，MPTP诱导的猕猴PD模型中，黑质区出现α-核突触蛋白的聚集（路易小体）和多巴胺能神经元的大量丢失，CDK5活性与表达增高，并出现大量的自噬。在C6细胞上进行的实验进一步证明MPTP诱导的自噬由CDK5介导。预先用褪黑素（脑白金的有效成分）处理能够拯救MPTP诱导的自噬和原代培养的神经元的树突长度和复杂度的降低，可以降低MPTP诱导的CDK5异常高表达。在小鼠中预先注射褪黑素或者脑室注射Cdk5基因的siRNA进行干扰后，能有效降低CDK5的表达并可阻断MPTP诱导的自噬、中脑黑质区的α-核突触蛋白的聚集和多巴胺能神经元的大量丢失，从而减轻MPTP的毒性作用，并最终阻断MPTP诱导的PD小鼠运动障碍。这些结果提示，褪黑素可阻断MPTP诱导的神经毒性和帕金森病症状，该作用机制很可能通过CDK5介导的自噬完成，该研究成果有望用于PD早期干预。
研究结果近期发表于自噬研究期刊Autophagy。
上述研究得到中国科学院脑功能联结图谱先导专项、“973”项目和国家自然科学基金委的资助。
图1 褪黑素预处理拯救MPTP导致的小鼠原代神经元的树突总长度和树突复杂度的降低
图2 褪黑素预处理或者脑室注射Cdk5基因siRNA可在小鼠中阻断MPTP诱导的运动障碍
图3 褪黑素通过抑制CDK5介导的自噬和SNCA聚集减轻MPTP的神经毒性
原文摘要：
Melatonin attenuates MPTP-induced neurotoxicity via preventing CDK5-mediated autophagy and SNCA/α-synuclein aggregation
Autophagy is involved in the pathogenesis of neurodegenerative diseases including Parkinson disease (PD). However, little is known about the regulation of autophagy in neurodegenerative process. In this study, we characterized aberrant activation of autophagy induced by neurotoxin 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) and demonstrated that melatonin has a protective effect on neurotoxicity. We found an excessive activation of autophagy in monkey brain tissues and C6 cells, induced by MPTP, which is mediated by CDK5 (cyclin-dependent kinase 5). MPTP treatment significantly reduced total dendritic length and dendritic complexity of cultured primary cortical neurons and melatonin could reverse this effect. Decreased TH (tyrosine hydroxylase)-positive cells and dendrites of dopaminergic neurons in the substantia nigra pars compacta (SNc) were observed in MPTP-treated monkeys and mice. Along with decreased TH protein level, we observed an upregulation of CDK5 and enhanced autophagic activity in the striatum of mice with MPTP injection. These changes could be salvaged by melatonin treatment or knockdown of CDK5. Importantly, melatonin or knockdown of CDK5 reduced MPTP-induced SNCA/α-synuclein aggregation in mice, which is widely thought to trigger the pathogenesis of PD. Finally, melatonin or knockdown of CDK5 counteracted the PD phenotype in mice induced by MPTP. Our findings uncover a potent role of CDK5-mediated autophagy in the pathogenesis of PD, and suggest that control of autophagic pathways may provide an important clue for exploring potential target for novel therapeutics of PD.
