Winklhofer K F, Tatzelt J
Department of Cellular Biochemistry, Max-Planck-Institute for Biochemistry, Martinsried, Germany.
Handb Exp Pharmacol. 2006(172):221-58. doi: 10.1007/3-540-29717-0_10.
The etiologies of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, polyglutamine diseases, or prion diseases may be diverse; however, aberrations in protein folding, processing, and/or degradation are common features of these entities, implying a role of quality control systems, such as molecular chaperones and the ubiquitin-proteasome pathway. There is substantial evidence for a causal role of protein misfolding in the pathogenic process coming from neuropathology, genetics, animal modeling, and biophysics. The presence of protein aggregates in all neurodegenerative diseases gave rise to the hypothesis that protein aggregates, be it intracellular or extracellular deposits, may perturb the cellular homeostasis and disintegrate neuronal function (Table 1). More recently, however, an increasing number of studies have indicated that protein aggregates are not toxic per se and might even serve a protective role by sequestering misfolded proteins. Specifically, experimental models of polyglutamine diseases, Alzheimer's disease, and Parkinson's disease revealed that the appearance of aggregates can be dissociated from neuronal toxicity, while misfolded monomers or oligomeric intermediates seem to be the toxic species. The unique features of molecular chaperones to assist in the folding of nascent proteins and to prevent stress-induced misfolding was the rationale to exploit their effects in different models of neurodegenerative diseases. This chapter concentrates on two neurodegenerative diseases, Parkinson's disease and prion diseases, with a special focus on protein misfolding and a possible role of molecular chaperones.
神经退行性疾病，如阿尔茨海默病、帕金森病、多聚谷氨酰胺疾病或朊病毒疾病，其病因可能多种多样；然而，蛋白质折叠、加工和/或降解异常是这些疾病的共同特征，这意味着分子伴侣和泛素-蛋白酶体途径等质量控制系统发挥了作用。来自神经病理学、遗传学、动物模型和生物物理学的大量证据表明，蛋白质错误折叠在致病过程中起因果作用。所有神经退行性疾病中蛋白质聚集体的存在引发了这样一种假说，即蛋白质聚集体，无论是细胞内沉积还是细胞外沉积，都可能扰乱细胞内稳态并破坏神经元功能（表1）。然而，最近越来越多的研究表明，蛋白质聚集体本身并无毒性，甚至可能通过隔离错误折叠的蛋白质起到保护作用。具体而言，多聚谷氨酰胺疾病、阿尔茨海默病和帕金森病的实验模型显示，聚集体的出现与神经元毒性可以分离，而错误折叠的单体或寡聚中间体似乎是有毒物种。分子伴侣协助新生蛋白质折叠并防止应激诱导的错误折叠的独特特性，是在不同神经退行性疾病模型中利用其作用的理论依据。本章重点关注两种神经退行性疾病，帕金森病和朊病毒疾病，特别关注蛋白质错误折叠以及分子伴侣可能发挥的作用。
