Division of Basic Neurosciences, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
Expert Rev Mol Med. 2011 Mar 21;13:e8. doi: 10.1017/S1462399411001803.
Macroautophagy and chaperone-mediated autophagy (CMA) are the two main mammalian lysosomal proteolytic systems. In macroautophagy, double-membrane structures engulf organelles and other intracellular constituents through a highly regulated process that involves the formation of autophagic vacuoles and their fusion with lysosomes. In CMA, selected proteins are targeted through a nonvesicular pathway to a transport complex at the lysosomal membrane, through which they are threaded into the lysosomes and degraded. Autophagy is important in development, differentiation, cellular remodelling and survival during nutrient starvation. Increasing evidence suggests that autophagic dysregulation causes accumulation of abnormal proteins or damaged organelles, which is a characteristic of chronic neurodegenerative conditions, such as Parkinson disease (PD). Evidence from post-mortem material, transgenic mice, and animal and cellular models of PD suggests that both major autophagic pathways are malfunctioning. Numerous connections exist between proteins genetically linked to autosomal dominant PD, in particular α-synuclein and LRRK2, and autophagic pathways. However, proteins involved in recessive PD, such as PINK1 and Parkin (PINK2), function in the process of mitophagy, whereby damaged mitochondria are selectively engulfed by macroautophagy. This wealth of new data suggests that both autophagic pathways are potential targets for therapeutic intervention in PD and other related neurodegenerative conditions.
自噬和伴侣介导的自噬（CMA）是哺乳动物溶酶体蛋白水解系统的两种主要形式。在自噬中，双层膜结构通过一个高度调控的过程吞噬细胞器和其他细胞内成分，这个过程涉及自噬小泡的形成和与溶酶体的融合。在 CMA 中，通过非囊泡途径将选定的蛋白质靶向溶酶体膜上的运输复合物，通过该复合物将它们穿入溶酶体并降解。自噬在发育、分化、细胞重塑和营养饥饿时的存活中起着重要作用。越来越多的证据表明，自噬失调会导致异常蛋白质或受损细胞器的积累，这是慢性神经退行性疾病（如帕金森病）的特征。来自尸检材料、转基因小鼠以及帕金森病的动物和细胞模型的证据表明，两种主要的自噬途径都存在功能障碍。与常染色体显性遗传帕金森病相关的许多蛋白质（特别是α-突触核蛋白和 LRRK2）与自噬途径之间存在许多联系。然而，涉及隐性帕金森病的蛋白质，如 PINK1 和 Parkin（PINK2），在细胞的线粒体自噬过程中发挥作用，即受损的线粒体被自噬选择性吞噬。大量新数据表明，自噬途径可能是帕金森病和其他相关神经退行性疾病治疗干预的潜在靶点。
