Proteomic Unit, Department of Psychiatry, Centre for Psychiatric Neuroscience, CHUV, CERY, Prilly-Lausanne, Switzerland.
Exp Biol Med (Maywood). 2011 Mar;236(3):268-76. doi: 10.1258/ebm.2010.010327. Epub 2011 Mar 7.
Today, Alzheimer's disease (AD) is one of the most important age-related neurodegenerative diseases, but its etiology remains still unknown. Since the discovery that the hallmark structures of this disease i.e. the formation of amyloid fibers could be the product of ubiquitin-mediated protein degradation defects, it has become clear that the ubiquitin-proteasome system (UPS), usually essential for protein repair, turnover and degradation, is perturbed in this disease. Different aspects of normal and pathological aging are discussed with respect to protein repair and degradation via the UPS, as well as consequences of a deficit in the UPS in AD. Selective protein oxidation may cause protein damage, or protein mutations may induce a dysfunction of the proteasome. Such events eventually lead to activation of cell death pathways and to an aberrant aggregation or incorporation of ubiquitinated proteins into hallmark structures. Aggresome formation is also observed in other neurodegenerative diseases, suggesting that an activation of similar mechanisms must occur in neurodegeneration as a basic phenomenon. It is essential to discuss therapeutic ways to investigate the UPS dysfunction in the human brain and to identify specific targets to hold or stop cell decay.
如今，阿尔茨海默病（AD）是最重要的与年龄相关的神经退行性疾病之一，但它的病因仍不清楚。自从发现这种疾病的标志性结构，即淀粉样纤维的形成可能是泛素介导的蛋白质降解缺陷的产物以来，人们已经清楚地认识到，泛素-蛋白酶体系统（UPS）通常对蛋白质的修复、周转和降解至关重要，在这种疾病中受到干扰。本文讨论了 UPS 对正常和病理性衰老的不同方面的影响，包括 UPS 对蛋白质修复和降解的影响，以及 UPS 缺陷在 AD 中的后果。选择性蛋白质氧化可能导致蛋白质损伤，或者蛋白质突变可能诱导蛋白酶体功能障碍。这些事件最终导致细胞死亡途径的激活，并导致异常聚集或标志性结构中泛素化蛋白质的掺入。在其他神经退行性疾病中也观察到聚集物的形成，这表明在神经退行性变中必须发生类似机制的激活，这是一个基本现象。探讨治疗方法以研究人类大脑中 UPS 功能障碍并确定特定的靶点以阻止或停止细胞衰退至关重要。
