Pacheco C, Aguayo L G, Opazo C
Laboratory of Neurobiometals, Department of Physiology, University of Concepción Concepción, Chile.
Front Physiol. 2012 Jul 26;3:297. doi: 10.3389/fphys.2012.00297. eCollection 2012.
Neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), and Dementia with Lewy bodies (DLB), display an accumulation of proteins including α-synuclein aggregates in cortical and subcortical regions of the brain. PD is a complex, progressive disease which involves damage of motor and cognitive brain regions, as well as autonomic and sensory areas. Since α-synuclein is a neuronal cytosolic protein, it is assumed that pathogenic changes induced by α-synuclein aggregates occur only at the cytoplasmic level. However, recent studies have identified the presence of extracellular α-synuclein, suggesting that the pathogenic action of this protein may also occur in the extracellular milieu through an unknown mechanism. One of the hypotheses is that extracellular α-synuclein aggregates or oligomers may directly disrupt the neuronal membrane by the formation of a pore reminiscent to the ones formed by β-amyloid aggregates. Here, we will review some evidence that support this mechanism, analyzing the interactions of α-synuclein with components of the plasma membrane, the formation of pore/perforated structures, and the implications on ionic dyshomeostasis. Furthermore, we will also discuss how this mechanism can be integrated into a general phenomenon that may explain the synaptotoxicity and neurotoxicity observed in different neurodegenerative diseases.
神经退行性疾病，如帕金森病（PD）、阿尔茨海默病（AD）和路易体痴呆（DLB），表现为大脑皮质和皮质下区域蛋白质的积累，包括α-突触核蛋白聚集体。帕金森病是一种复杂的进行性疾病，涉及大脑运动和认知区域以及自主神经和感觉区域的损伤。由于α-突触核蛋白是一种神经元胞质蛋白，因此推测α-突触核蛋白聚集体引起的致病变化仅发生在细胞质水平。然而，最近的研究已经确定了细胞外α-突触核蛋白的存在，这表明这种蛋白质的致病作用也可能通过未知机制在细胞外环境中发生。其中一个假说是，细胞外α-突触核蛋白聚集体或寡聚体可能通过形成类似于β-淀粉样蛋白聚集体形成的孔来直接破坏神经元膜。在这里，我们将回顾一些支持这一机制的证据，分析α-突触核蛋白与质膜成分的相互作用、孔/穿孔结构的形成以及对离子稳态失调的影响。此外，我们还将讨论这一机制如何融入一个普遍现象，该现象可能解释在不同神经退行性疾病中观察到的突触毒性和神经毒性。
