Department of Neuropathology, Faculty of Life and Medical Science, Doshisha University, Kyoto, Japan.
Cold Spring Harb Perspect Med. 2012 Aug 1;2(8):a006361. doi: 10.1101/cshperspect.a006361.
As neurons age, their survival depends on eliminating a growing burden of damaged, potentially toxic proteins and organelles-a capability that declines owing to aging and disease factors. Here, we review the two proteolytic systems principally responsible for protein quality control in neurons and their important contributions to Alzheimer disease pathogenesis. In the first section, the discovery of paired helical filament ubiquitination is described as a backdrop for discussing the importance of the ubiquitin-proteasome system in Alzheimer disease. In the second section, we review the prominent involvement of the lysosomal system beginning with pathological endosomal-lysosomal activation and signaling at the very earliest stages of Alzheimer disease followed by the progressive failure of autophagy. These abnormalities, which result in part from Alzheimer-related genes acting directly on these lysosomal pathways, contribute to the development of each of the Alzheimer neuropathological hallmarks and represent a promising therapeutic target.
随着神经元的衰老，它们的存活取决于消除不断增加的受损、潜在有毒的蛋白质和细胞器的负担——由于衰老和疾病因素，这种能力会下降。在这里，我们回顾了主要负责神经元蛋白质质量控制的两种蛋白水解系统及其对阿尔茨海默病发病机制的重要贡献。在第一节中，描述了配对螺旋丝泛素化的发现，以此作为讨论泛素-蛋白酶体系统在阿尔茨海默病中的重要性的背景。在第二节中，我们从阿尔茨海默病早期阶段病理性内体-溶酶体激活和信号开始，综述了溶酶体系统的突出作用，随后是自噬的逐渐失效。这些异常部分是由于与阿尔茨海默病相关的基因直接作用于这些溶酶体途径所致，导致了阿尔茨海默病神经病理学特征的每一个发展，并代表了一个有前途的治疗靶点。
