Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
Department of Drug Sciences, Pharmacology Section, University of Pavia, Pavia, Italy.
Ageing Res Rev. 2014 Nov;18:16-28. doi: 10.1016/j.arr.2014.07.002. Epub 2014 Jul 22.
Processing of misfolded proteins is important in order for the cell to maintain its normal functioning and homeostasis. Three systems control the quality of proteins: chaperone-mediated refolding, proteasomal degradation of ubiquitinated proteins, and finally, when the two others fail, aggrephagy, as selective form of autophagy, degrades ubiquitin-labelled aggregated cargos. In this route misfolded proteins gradually form larger aggregates, aggresomes and they eventually become double membrane-wrapped organelles called autophagosomes, which become degraded when they fuse to lysosomes, for reuse by the cell. The stages, the main molecules participating in the process, and the regulation of aggrephagy are discussed here, as is the role of protein aggregation in protein accumulation diseases. In particular, we emphasize that both Alzheimer's disease and age-related macular degeneration, two of the most common pathologies in the aged, are characterized by altered protein clearance and deposits. Based on the hypothesis that manipulations of autophagy may be potentially useful in these and other aggregation-related diseases, we will discuss some promising therapeutic strategies to counteract protein aggregates-induced cellular toxicity.
为了维持细胞的正常功能和内稳态，错误折叠的蛋白质的处理是很重要的。有三个系统控制蛋白质的质量：伴侣介导的重折叠、泛素化蛋白的蛋白酶体降解，以及当另外两个系统失效时，选择性自噬形式的聚集体ophagy 降解泛素化标记的聚集体货物。在这条途径中，错误折叠的蛋白质逐渐形成更大的聚集体、聚集体，最终成为双层膜包裹的细胞器，称为自噬体，当它们与溶酶体融合时被降解，以供细胞重新利用。本文讨论了聚集体ophagy 的阶段、参与该过程的主要分子以及其调控，以及蛋白质聚集在蛋白质积累疾病中的作用。特别是，我们强调阿尔茨海默病和年龄相关性黄斑变性这两种老年人中最常见的病理之一的特征是蛋白质清除和沉积的改变。基于自噬的操纵可能对这些和其他与聚集相关的疾病有潜在用途的假设，我们将讨论一些有前途的治疗策略，以对抗蛋白质聚集诱导的细胞毒性。
