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Implications of peptide assemblies in amyloid diseases
Chemical Society Reviews ( IF 46.2 ) Pub Date : 2017-07-12 00:00:00 , DOI: 10.1039/c7cs00372b
Pu Chun Ke 1, 2, 3, 4, 5 , Marc-Antonie Sani 4, 5, 6, 7, 8 , Feng Ding 9, 10, 11, 12 , Aleksandr Kakinen 1, 2, 3, 4, 5 , Ibrahim Javed 1, 2, 3, 4, 5 , Frances Separovic 4, 5, 6, 7, 8 , Thomas P. Davis 1, 2, 3, 4, 5 , Raffaele Mezzenga 13, 14, 15, 16
Affiliation  

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:

肽组装体在淀粉样变性疾病中的意义

神经退行性疾病和2型糖尿病是全球性的流行病,危害着全球数以百万计的人们的生活质量,具有深远的社会和经济意义。尽管病理学上存在显着差异-许多尚不清楚,但这些疾病通常以交叉β淀粉样蛋白原纤维的存在以及神经元或胰腺β细胞的丢失为特征。在这篇综述中,我们记录了淀粉样β,α突触核蛋白,人类胰岛淀粉样多肽和病毒,与阿尔茨海默氏症,帕金森氏症,2型糖尿病和病毒疾病相关的肽和蛋白质的分子和介观自组装研究进展。此外,我们根据淀粉样蛋白的自组装以及它们与膜,金属离子,小分子和工程化的纳米粒子。通过本次演讲,我们展示了淀粉样蛋白通过一级和二级成核,从无序单体到α螺旋,然后在蛋白遇到细胞膜时向β-折叠的共同进化,在淀粉样蛋白的结构转变方面存在着显着的异同。共识(少数例外)是,无论致病蛋白序列或理化性质如何,非途径的寡聚体而不是淀粉样原纤维都是有毒物种。此外,我们强调了分子自组装在引起淀粉样蛋白在其细胞环境及其在细胞和器官之间扩散的背景下的生物学和病理学后果中的关键作用。
更新日期:2017-10-30
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