Agnati L F, Baldelli E, Andreoli N, Woods A S, Vellani V, Marcellino D, Guidolin D, Fuxe K
Section of Physiology, Department of Biomedical Sciences, University of Modena, 41100 Modena, Italy.
J Neural Transm (Vienna). 2008 Sep;115(9):1285-99. doi: 10.1007/s00702-008-0072-1. Epub 2008 Jun 5.
On the basis of the previously proposed hierarchic organisation of the central nervous system (CNS) and of its syntropic behaviour, a view of neurodegenerative diseases focusing on the assemblage of abnormal multimeric proteins (pathologic protein mosaics (PMs)) is proposed. Thus, the main focus of the present paper is on Parkinson's disease (PD) as a neurodegenerative disease, which has as crucial feature protein conformational alterations and formation of pathological PMs. Two interconnected cellular dysfunctions are discussed as main pathogenic factors of PD syndromes, namely mitochondrial deficits (i.e. energy failure, especially critical for Substantia Nigra DA neurons) and conformational protein alterations (due to genetic or environmental causes). Conformational protein alterations can trigger pathological phenomena via the loss and/or the gain of new functions. In particular, altered proteins can lead to the formation of abnormal PMs, which can, inter alia, cause distortion of cellular structures, toxic functions and/or formation of improper membrane ion channels. In view of the fact that disordered proteins can easily acquire unwanted conformation, the "disorder index" (DI) for proteins involved in PD has been evaluated. It has been found that both alpha-synuclein and tau-protein have high DI. This datum is in agreement with the observation that these two proteins synergistically promote polymerisation of each other into amyloid fibrils, favouring the formation of Lewy bodies.
基于先前提出的中枢神经系统（CNS）的层级组织及其同向行为，本文提出了一种关于神经退行性疾病的观点，该观点聚焦于异常多聚体蛋白（病理性蛋白镶嵌体（PMs））的聚集。因此，本文的主要重点是帕金森病（PD）这一神经退行性疾病，其关键特征是蛋白质构象改变和病理性PMs的形成。本文讨论了两种相互关联的细胞功能障碍，它们是PD综合征的主要致病因素，即线粒体缺陷（即能量衰竭，对黑质多巴胺能神经元尤为关键）和构象性蛋白质改变（由遗传或环境原因引起）。构象性蛋白质改变可通过新功能的丧失和/或获得引发病理现象。特别是，改变的蛋白质可导致异常PMs的形成，这尤其会导致细胞结构扭曲、毒性功能和/或不适当的膜离子通道形成。鉴于无序蛋白质容易获得不需要的构象，已对参与PD的蛋白质的“无序指数”（DI）进行了评估。已发现α-突触核蛋白和tau蛋白均具有高DI。这一数据与以下观察结果一致，即这两种蛋白质协同促进彼此聚合成淀粉样纤维，有利于路易小体的形成。
