Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom.
Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom; Cavendish Laboratory, University of Cambridge, J J Thomson Avenue, Cambridge CB3 0HE, United Kingdom.
Biochim Biophys Acta Biomembr. 2021 Apr 1;1863(4):183536. doi: 10.1016/j.bbamem.2020.183536. Epub 2020 Dec 26.
Parkinson's disease is an increasingly prevalent and currently incurable neurodegenerative disorder. At the molecular level, this disease is characterized by the formation of aberrant intracellular protein deposits known as Lewy bodies. Oligomeric forms of the protein α-synuclein (αS), which are believed to be both intermediates and by-products of Lewy body formation, are considered to be the main pathogenic species. Interactions of such oligomers with lipid membranes are increasingly emerging as a major molecular pathway underpinning their toxicity. Here we review recent progress in our understanding of the interactions of αS oligomers with lipid membranes. We highlight key structural and biophysical features of αS oligomers, the effects of these features on αS oligomer membrane binding properties, and resultant implications for understanding the etiology of Parkinson's disease. We discuss mechanistic modes of αS oligomer-lipid membrane interactions and the effects of environmental factors to such modes. Finally, we provide an overview of the current understanding of the main molecular determinants of αS oligomer toxicity in vivo.
帕金森病是一种日益流行且目前无法治愈的神经退行性疾病。在分子水平上，这种疾病的特征是形成异常的细胞内蛋白质沉积物，称为路易体。α-突触核蛋白（αS）的寡聚形式，被认为是路易体形成的中间产物和副产物，被认为是主要的致病物质。这些寡聚体与脂膜的相互作用，正逐渐成为其毒性的主要分子途径。在这里，我们回顾了我们对αS 寡聚体与脂膜相互作用的理解的最新进展。我们强调了αS 寡聚体的关键结构和生物物理特征、这些特征对αS 寡聚体膜结合特性的影响，以及对理解帕金森病病因学的影响。我们讨论了αS 寡聚体-脂膜相互作用的机制模式及其对环境因素的影响。最后，我们概述了目前对αS 寡聚体在体内毒性的主要分子决定因素的理解。
