Neurodegenerative disorders and type 2 diabetes are global epidemics compromising the quality of life of millions worldwide, with profound social and economic implications. Despite the significant differences in pathology – much of which are poorly understood – these diseases are commonly characterized by the presence of cross-β amyloid fibrils as well as the loss of neuronal or pancreatic β-cells. In this review, we document research progress on the molecular and mesoscopic self-assembly of amyloid-beta, alpha synuclein, human islet amyloid polypeptide and prions, the peptides and proteins associated with Alzheimer's, Parkinson's, type 2 diabetes and prion diseases. In addition, we discuss the toxicities of these amyloid proteins based on their self-assembly as well as their interactions with membranes, metal ions, small molecules and engineered nanoparticles. Through this presentation we show the remarkable similarities and differences in the structural transitions of the amyloid proteins through primary and secondary nucleation, the common evolution from disordered monomers to alpha-helices and then to β-sheets when the proteins encounter the cell membrane, and, the consensus (with a few exceptions) that off-pathway oligomers, rather than amyloid fibrils, are the toxic species regardless of the pathogenic protein sequence or physicochemical properties. In addition, we highlight the crucial role of molecular self-assembly in eliciting the biological and pathological consequences of the amyloid proteins within the context of their cellular environments and their spreading between cells and organs. Exploiting such structure–function–toxicity relationship may prove pivotal for the detection and mitigation of amyloid diseases.

中文翻译：

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肽组装在淀粉样蛋白疾病中的意义

神经退行性疾病和 2 型糖尿病是全球流行病，影响着全世界数百万人的生活质量，具有深远的社会和经济影响。尽管病理学存在显着差异（其中大部分尚不清楚），但这些疾病的共同特征是存在交叉 β 淀粉样原纤维以及神经元或胰腺 β 细胞的损失。在这篇综述中，我们记录了β淀粉样蛋白、α突触核蛋白、人胰岛淀粉样蛋白多肽和朊病毒、与阿尔茨海默氏症、帕金森氏症、2型糖尿病和朊病毒病相关的肽和蛋白质的分子和介观自组装的研究进展。此外，我们还根据这些淀粉样蛋白的自组装以及它们与膜、金属离子、小分子和工程纳米颗粒的相互作用来讨论它们的毒性。通过本次演讲，我们展示了淀粉样蛋白通过初级和次级成核的结构转变的显着相似性和差异，以及当蛋白质遇到细胞膜时从无序单体到α螺旋再到β折叠的共同进化，以及，人们一致认为，无论致病蛋白序列或理化性质如何，非途径寡聚体，而不是淀粉样原纤维，都是有毒物质。此外，我们强调了分子自组装在淀粉样蛋白在其细胞环境及其在细胞和器官之间传播的背景下引发生物学和病理学后果中的关键作用。利用这种结构-功能-毒性关系可能对于淀粉样蛋白疾病的检测和缓解至关重要。