Gonzalez-Garcia Mario, Fusco Giuliana, De Simone Alfonso
Department of Life Sciences, Imperial College London, South Kensington, United Kingdom.
Department of Chemistry, Centre for Misfolding Diseases, University of Cambridge, Cambridge, United Kingdom.
Front Cell Dev Biol. 2021 Mar 11;9:642623. doi: 10.3389/fcell.2021.642623. eCollection 2021.
The conversion of otherwise soluble proteins into insoluble amyloid aggregates is associated with a range of neurodegenerative disorders, including Alzheimer's and Parkinson's diseases, as well as non-neuropathic conditions such as type II diabetes and systemic amyloidoses. It is increasingly evident that the most pernicious species among those forming during protein aggregation are small prefibrillar oligomers. In this review, we describe the recent progress in the characterization of the cellular and molecular interactions by toxic misfolded protein oligomers. A fundamental interaction by these aggregates involves biological membranes, resulting in two major model mechanisms at the onset of the cellular toxicity. These include the membrane disruption model, resulting in calcium imbalance, mitochondrial dysfunction and intracellular reactive oxygen species, and the direct interaction with membrane proteins, leading to the alteration of their native function. A key challenge remains in the characterization of transient interactions involving heterogeneous protein aggregates. Solving this task is crucial in the quest of identifying suitable therapeutic approaches to suppress the cellular toxicity in protein misfolding diseases.
原本可溶的蛋白质转变为不溶性淀粉样聚集体与一系列神经退行性疾病相关，包括阿尔茨海默病和帕金森病，以及非神经病变状况，如II型糖尿病和全身性淀粉样变性。越来越明显的是，在蛋白质聚集过程中形成的最有害的物种是小的原纤维前体寡聚物。在这篇综述中，我们描述了有毒错误折叠蛋白寡聚物在细胞和分子相互作用表征方面的最新进展。这些聚集体的一种基本相互作用涉及生物膜，在细胞毒性开始时产生两种主要的模型机制。其中包括膜破坏模型，导致钙失衡、线粒体功能障碍和细胞内活性氧，以及与膜蛋白的直接相互作用，导致其天然功能改变。在涉及异质蛋白质聚集体的瞬时相互作用表征方面，一个关键挑战仍然存在。解决这一任务对于寻找合适的治疗方法以抑制蛋白质错误折叠疾病中的细胞毒性至关重要。
