Department of Neurology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Mol Neurobiol. 2013 Apr;47(2):466-83. doi: 10.1007/s12035-012-8327-0. Epub 2012 Aug 31.
Parkinson's disease (PD) is a progressive neurodegenerative disorder affecting ~1 % of people over the age of 65. Neuropathological hallmarks of PD are prominent loss of dopaminergic (DA) neurons in the substantia nigra and formation of intraneuronal protein inclusions termed Lewy bodies, composed mainly of α-synuclein (αSyn). Missense mutations in αSyn gene giving rise to production of degradation-resistant mutant proteins or multiplication of wild-type αSyn gene allele can cause rare inherited forms of PD. Therefore, the existence of abnormally high amount of αSyn protein is considered responsible for the DA neuronal death in PD. Normally, αSyn protein localizes to presynaptic terminals of neuronal cells, regulating the neurotransmitter release through the modulation of assembly of soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex. On the other hand, of note, pathological examinations on the recipient patients of fetal nigral transplants provided a prion-like cell-to-cell transmission hypothesis for abnormal αSyn. The extracellular αSyn fibrils can internalize to the cells and enhance intracellular formation of protein inclusions, thereby reducing cell viability. These findings suggest that effective removal of abnormal species of αSyn in the extracellular space as well as intracellular compartments can be of therapeutic relevance. In this review, we will focus on αSyn-triggered neuronal cell death and provide possible disease-modifying therapies targeting abnormally accumulating αSyn.
帕金森病（PD）是一种进行性神经退行性疾病，影响 65 岁以上人群的 1%左右。PD 的神经病理学标志是黑质中多巴胺能（DA）神经元的明显丧失和称为路易体的细胞内蛋白包涵体的形成，主要由α-突触核蛋白（αSyn）组成。αSyn 基因的错义突变导致产生降解抗性的突变蛋白或野生型 αSyn 基因等位基因的倍增可能导致罕见的遗传性 PD 形式。因此，异常高水平的αSyn 蛋白被认为是 PD 中 DA 神经元死亡的原因。正常情况下，αSyn 蛋白定位于神经元细胞的突触前末端，通过调节可溶性 N-乙基马来酰亚胺敏感因子附着蛋白受体复合物的组装来调节神经递质的释放。另一方面，值得注意的是，对胎儿黑质移植接受者的病理检查提供了一个异常αSyn 的朊病毒样细胞间传播假说。细胞外的αSyn 纤维可以内化到细胞中，并增强细胞内蛋白包涵体的形成，从而降低细胞活力。这些发现表明，有效去除细胞外空间和细胞内隔室中异常的αSyn 物种可能具有治疗相关性。在这篇综述中，我们将重点讨论αSyn 引发的神经元细胞死亡，并提供针对异常积累的αSyn 的可能的疾病修饰治疗方法。
