GenieUs Genomics, Sydney, NSW 2010, Australia; University of New South Wales, Sydney, NSW 2052, Australia.
GenieUs Genomics, Sydney, NSW 2010, Australia.
Int J Biol Macromol. 2021 Jun 30;181:582-604. doi: 10.1016/j.ijbiomac.2021.03.113. Epub 2021 Mar 23.
Many neurodegenerative diseases are rooted in the activities of amyloid-like proteins which possess conformations that spread to healthy proteins. These include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). While their clinical manifestations vary, their protein-level mechanisms are remarkably similar. Aberrant monomeric proteins undergo conformational shifts, facilitating aggregation and formation of solid fibrils. However, there is growing evidence that intermediate oligomeric stages are key drivers of neuronal toxicity. Analysis of protein dynamics is complicated by the fact that nucleation and growth of amyloid-like proteins is not a linear pathway. Feedback within this pathway results in exponential acceleration of aggregation, but activities exerted by oligomers and fibrils can alter cellular interactions and the cellular environment as a whole. The resulting cascade of effects likely contributes to the late onset and accelerating progression of amyloid-like protein disorders and the widespread effects they have on the body. In this review we explore the amyloid-like proteins associated with AD, PD, HD and ALS, as well as the common mechanisms of amyloid-like protein nucleation and aggregation. From this, we identify core elements of pathological progression which have been targeted for therapies, and which may become future therapeutic targets.
许多神经退行性疾病都源于淀粉样蛋白样蛋白的活性，这些蛋白具有能够扩散到健康蛋白的构象。其中包括阿尔茨海默病（AD）、帕金森病（PD）、亨廷顿病（HD）和肌萎缩性侧索硬化症（ALS）。尽管它们的临床表现不同，但它们在蛋白质水平上的机制非常相似。异常的单体蛋白会发生构象转变，促进聚集和固态原纤维的形成。然而，越来越多的证据表明，中间寡聚阶段是神经元毒性的关键驱动因素。由于淀粉样蛋白样蛋白的成核和生长不是线性途径，因此分析蛋白质动力学非常复杂。该途径内的反馈会导致聚集的指数加速，但寡聚体和原纤维的活性会改变细胞间的相互作用和整个细胞环境。由此产生的一系列影响可能导致淀粉样蛋白样蛋白紊乱的发病晚和进展加速，以及它们对身体的广泛影响。在这篇综述中，我们探讨了与 AD、PD、HD 和 ALS 相关的淀粉样蛋白样蛋白，以及淀粉样蛋白样蛋白成核和聚集的常见机制。从中，我们确定了病理进展的核心要素，这些要素已成为治疗的目标，并且可能成为未来的治疗靶点。
