Department of Biochemical Sciences and Research Centre on the Molecular Basis of Neurodegeneration, University of Florence, V.le Morgagni 50, 50134 Florence, Italy.
Prog Neurobiol. 2012 Dec;99(3):226-45. doi: 10.1016/j.pneurobio.2012.03.002. Epub 2012 Mar 23.
Amyloid diseases display the presence, in targeted tissues and organs, of fibrillar deposits of specific peptides or proteins. Increasing efforts are presently spent in investigating the structural features and the structure-toxicity relation of the soluble oligomeric precursors arising in the path of fibrillization as well as the importance of surfaces as triggers of protein misfolding and aggregation and as possible responsible for amyloid polymorphism. Presently, it is recognized that the unstable, heterogeneous pre-fibrillar aggregates are the main responsible for amyloid toxicity. Conversely, mature fibrils are considered stable, harmless reservoirs of toxic species, although direct fibril toxicity has been reported. Recent studies show that mature fibrils grown at various conditions can display different structural features, stabilities and tendency to disassemble with leak of toxic oligomers. Fibril polymorphism can result from protein aggregation at differing conditions populating misfolded monomers and oligomers with distinct conformational characteristics. Recent research has started to unravel oligomer structural and biophysical features and their relation to cytotoxicity. Increasing information supports the notion that oligomer-membrane interaction, disruption of membrane integrity and cell impairment results from both oligomer and membrane biophysical features; accordingly, the formation of the oligomer-membrane complex, often the first step of amyloid toxicity, can be the result of the interplay of these events. This view can help explaining the variable vulnerability of different cell types to the same amyloids and the lack of relation between amyloid load and severity of clinical symptoms; it also stresses the importance, for cell/tissue impairment, of the presence of fibrils conformers of reduced stability as a possible source of oligomers resulting from leakage possibly favored by the interaction with suitable macromolecular/lipid surfaces or by other environmental conditions.
淀粉样变性疾病表现为特定肽或蛋白质的纤维状沉积物在靶向组织和器官中的存在。目前，人们正在投入更多的努力来研究纤维形成过程中可溶性寡聚体前体的结构特征和结构-毒性关系，以及表面作为蛋白质错误折叠和聚集的触发因素以及可能导致淀粉样蛋白多态性的重要性。目前，人们认识到不稳定的、异质的预纤维状聚集体是淀粉样毒性的主要原因。相反，成熟的纤维被认为是稳定的、无害的毒性物质储存库，尽管已经报道了直接纤维毒性。最近的研究表明，在不同条件下生长的成熟纤维可以表现出不同的结构特征、稳定性和与毒性寡聚物泄漏的解组装倾向。纤维的多态性可能是由于在不同条件下的蛋白质聚集，导致具有不同构象特征的错误折叠单体和寡聚物的聚集。最近的研究已经开始揭示寡聚物的结构和生物物理特征及其与细胞毒性的关系。越来越多的信息支持这样一种观点，即寡聚物-膜相互作用、膜完整性的破坏和细胞损伤是由寡聚物和膜生物物理特征共同作用的结果；因此，寡聚物-膜复合物的形成，通常是淀粉样毒性的第一步，可能是这些事件相互作用的结果。这种观点可以帮助解释不同细胞类型对相同淀粉样蛋白的易感性差异以及淀粉样蛋白负荷与临床症状严重程度之间缺乏关系；它还强调了对于细胞/组织损伤，具有降低稳定性的纤维构象的存在作为可能来自于寡聚物泄漏的来源的重要性，这种泄漏可能是由于与合适的大分子/脂质表面的相互作用或其他环境条件而更容易发生。
