Rcom-H'cheo-Gauthier Alexandre N, Osborne Samantha L, Meedeniya Adrian C B, Pountney Dean L
Menzies Health Institute Queensland, Griffith University Gold Coast, QLD, Australia.
Front Neurosci. 2016 Dec 20;10:570. doi: 10.3389/fnins.2016.00570. eCollection 2016.
Aggregation of the pre-synaptic protein, α-synuclein (α-syn), is the key etiological factor in Parkinson's disease (PD) and other alpha-synucleinopathies, such as multiple system atrophy (MSA) and Dementia with Lewy bodies (DLB). Various triggers for pathological α-syn aggregation have been elucidated, including post-translational modifications, oxidative stress, and binding of metal ions, such as calcium. Raised neuronal calcium levels in PD may occur due to mitochondrial dysfunction and/or may relate to calcium channel dysregulation or the reduced expression of the neuronal calcium buffering protein, calbindin-D28k. Recent results on human tissue and a mouse oxidative stress model show that neuronal calbindin-D28k expression excludes α-syn inclusion bodies. Previously, cell culture model studies have shown that transient increases of intracellular free Ca(II), such as by opening of the voltage-gated plasma calcium channels, could induce cytoplasmic aggregates of α-syn. Raised intracellular free calcium and oxidative stress also act cooperatively to promote α-syn aggregation. The association between raised neuronal calcium, α-syn aggregation, oxidative stress, and neurotoxicity is reviewed in the context of neurodegenerative α-syn disease and potential mechanism-based therapies.
突触前蛋白α-突触核蛋白（α-syn）的聚集是帕金森病（PD）和其他α-突触核蛋白病（如多系统萎缩症（MSA）和路易体痴呆症（DLB））的关键病因。已经阐明了病理性α-syn聚集的各种触发因素，包括翻译后修饰、氧化应激以及金属离子（如钙）的结合。PD中神经元钙水平升高可能是由于线粒体功能障碍引起的，和/或可能与钙通道失调或神经元钙缓冲蛋白钙结合蛋白-D28k的表达降低有关。关于人体组织和小鼠氧化应激模型的最新研究结果表明，神经元钙结合蛋白-D28k的表达可排除α-syn包涵体。此前，细胞培养模型研究表明，细胞内游离Ca（II）的短暂增加，如通过电压门控性血浆钙通道的开放，可诱导α-syn的细胞质聚集。细胞内游离钙升高和氧化应激也协同作用促进α-syn聚集。在神经退行性α-syn疾病和基于潜在机制的治疗方法的背景下，对神经元钙升高、α-syn聚集、氧化应激和神经毒性之间的关联进行了综述。
