Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Cold Spring Harb Perspect Biol. 2011 Jul 1;3(7):a004457. doi: 10.1101/cshperspect.a004457.
Over the last three decades, advances in biochemical pathology and human genetics have illuminated one of the most enigmatic subjects in biomedicine--neurodegeneration. Eponymic diseases of the nervous system such as Alzheimer's, Parkinson's, and Huntington's diseases that were long characterized by mechanistic ignorance have yielded striking progress in our understanding of their molecular underpinnings. A central theme in these and related disorders is the concept that certain normally soluble neuronal proteins can misfold and aggregate into oligomers and amyloid fibrils which can confer profound cytotoxicity. Perhaps the foremost example, both in terms of its societal impact and how far knowledge has moved toward the clinic, is that of Alzheimer's disease (AD). Here, we will review the classical protein lesions of the disorder that have provided a road map to etiology and pathogenesis. We will discuss how elucidating the genotype-to-phenotype relationships of familial forms of Alzheimer's disease has highlighted the importance of the misfolding and altered proteostasis of two otherwise soluble proteins, amyloid β-protein and tau, suggesting mechanism-based therapeutic targets that have led to clinical trials.
在过去的三十年中，生物化学病理学和人类遗传学的进步揭示了生物医学中最神秘的课题之一——神经退行性疾病。长期以来，神经系统的神经退行性疾病（如阿尔茨海默病、帕金森病和亨廷顿病）的特征是机制上的无知，而这些疾病在理解其分子基础方面取得了惊人的进展。这些疾病和相关疾病的一个核心主题是，某些正常可溶性神经元蛋白可以错误折叠并聚集形成寡聚物和淀粉样纤维，从而产生严重的细胞毒性。也许最重要的例子，无论是在其对社会的影响方面，还是在知识向临床推进的程度方面，都是阿尔茨海默病（AD）。在这里，我们将回顾该疾病的经典蛋白病变，这些病变为病因和发病机制提供了路线图。我们将讨论阐明家族性阿尔茨海默病的基因型到表型关系如何突出了两种可溶性蛋白——淀粉样β蛋白和 tau 的错误折叠和异常蛋白质稳定性的重要性，这表明基于机制的治疗靶点已导致临床试验。
