Miraglia Fabiana, Betti Laura, Palego Lionella, Giannaccini Gino
Department of Pharmacy, University of Pisa, Via Bonanno 6, P.O. Box: 56126, Pisa, Italy.
Cent Nerv Syst Agents Med Chem. 2015;15(2):109-16. doi: 10.2174/1871524915666150421114338.
Parkinson's Disease (PD) and alpha synucleinopathies are multifactorial disorders, which manifest through motor symptoms and non-motor symptoms involving the Central Nervous System (CNS), the Peripheral Nervous System (PNS) and, recently, also the Enteric Nervous System (ENS). The typical hallmarks of alpha synucleinopathies are proteinaceous inclusions of alpha synuclein (αS). In PD they are known as Lewy Bodies (LBs) and Lewy Neurites (LNs), discovered in dopaminergic neurons of substantia nigra (pars compacta) as well as in other regions of the central and peripheral nervous systems. Despite the clear causes which lead to LBs/LNs are still unknown, according to Braak's theory, these inclusions appear first in PNS to spread, following neuronal innervation, towards the CNS in a spatio- temporal dissemination described in a staging procedure. In line with these observations, several animal models have been used with the purpose to reproduce PD as well as to propose new therapeutic approaches. Different pathways can cooperate to neurodegeneration in PD such as genetic mutations of αS gene, mitochondrial dysfunctions, neuroinflammation. The present review highlights αS as the key-word for PD pathology and alpha synucleinopathies and a main target in PD research. Several therapeutic approaches can be proposed, however all of them are addressed in advanced stages of the pathology. Our focus will be the alteration of αS physiological pathway, which allows to address therapy in early stages at intracellular or extracellular level, such as the use of anti ER-stress compounds and innovative immunotherapy, which could be promising tools to reduce neuronal degeneration and to halt PD progression.
帕金森病（PD）和α-突触核蛋白病是多因素疾病，通过涉及中枢神经系统（CNS）、外周神经系统（PNS）以及最近发现的肠神经系统（ENS）的运动症状和非运动症状表现出来。α-突触核蛋白病的典型特征是α-突触核蛋白（αS）的蛋白质包涵体。在帕金森病中，它们被称为路易小体（LBs）和路易神经突（LNs），在黑质致密部的多巴胺能神经元以及中枢和外周神经系统的其他区域被发现。尽管导致路易小体/路易神经突形成的确切原因仍不清楚，但根据布拉克理论，这些包涵体首先出现在外周神经系统，然后随着神经元支配，按照分期程序中描述的时空传播方式向中枢神经系统扩散。与这些观察结果一致，已经使用了几种动物模型来重现帕金森病并提出新的治疗方法。帕金森病中的神经退行性变可通过多种途径协同作用，如αS基因的基因突变、线粒体功能障碍、神经炎症。本综述强调αS是帕金森病病理学和α-突触核蛋白病的关键词，也是帕金森病研究的主要靶点。可以提出几种治疗方法，然而所有这些方法都针对疾病的晚期阶段。我们的重点将是改变αS的生理途径，这使得能够在细胞内或细胞外水平的早期阶段进行治疗，例如使用抗内质网应激化合物和创新的免疫疗法，这可能是减少神经元变性和阻止帕金森病进展的有前途的工具。
