Smith David M
Department of Biochemistry, School of Medicine, West Virginia University, Morgantown, WV, USA.
J Exp Neurosci. 2018 Aug 19;12:1179069518794675. doi: 10.1177/1179069518794675. eCollection 2018.
At the cellular level, many neurodegenerative diseases (NDs), often considered proteinopathies, are characterized by the accumulation of misfolded and damaged proteins into large insoluble aggregates. Prominent species that accumulate early and play fundamental roles in disease pathogenesis are amyloid β (Aβ) and tau in Alzheimer disease, α-synuclein (α-syn) in Parkinson disease, and polyQ-expanded huntingtin (Htt) in Huntington disease. Although significant efforts have focused on how the cell deals with these protein aggregates, why is it that these misfolded proteins are not degraded normally in the first place? A vast body of literature supports the notion that the cell's protein degradation system for individual proteins-the ubiquitin proteasome system (UPS)-does not function sufficiently in many NDs. The proteasome itself has received significant focus for years due to its obvious failure to degrade misfolded proteins in ND, but no general mechanism has been uncovered. We have recently found that specific pathologically relevant oligomers can potently and directly inhibit the proteasome. What is most interesting is that the misfolded protein's primary amino acid sequence was irrelevant to its ability to inhibit. Instead, the culprit is the 3-dimensional shape of the misfolded oligomers. It turns out that many misfolded proteins in ND can take on this proteasome-impairing shape suggesting that there could be a common mechanism for UPS impairment in many NDs. The proteasome is already an important target for treating cancer, could it also be targeted to broadly treat ND?
在细胞水平上，许多通常被认为是蛋白质病的神经退行性疾病（NDs）的特征是错误折叠和受损的蛋白质积累形成大的不溶性聚集体。在疾病发病机制中早期积累并起基本作用的突出物质包括阿尔茨海默病中的淀粉样β蛋白（Aβ）和tau蛋白、帕金森病中的α-突触核蛋白（α-syn）以及亨廷顿病中的多聚谷氨酰胺扩展的亨廷顿蛋白（Htt）。尽管已经做出了巨大努力来研究细胞如何处理这些蛋白质聚集体，但为什么这些错误折叠的蛋白质一开始就不能被正常降解呢？大量文献支持这样一种观点，即细胞针对单个蛋白质的蛋白质降解系统——泛素蛋白酶体系统（UPS）——在许多神经退行性疾病中功能不足。多年来，蛋白酶体本身一直备受关注，因为它显然无法在神经退行性疾病中降解错误折叠的蛋白质，但尚未发现普遍机制。我们最近发现，特定的与病理相关的寡聚体可以有效且直接地抑制蛋白酶体。最有趣的是，错误折叠蛋白质的一级氨基酸序列与其抑制能力无关。相反，罪魁祸首是错误折叠寡聚体的三维形状。事实证明，神经退行性疾病中的许多错误折叠蛋白质都能呈现这种损害蛋白酶体的形状，这表明在许多神经退行性疾病中可能存在泛素蛋白酶体系统受损的共同机制。蛋白酶体已经是治疗癌症的重要靶点，它是否也能成为广泛治疗神经退行性疾病的靶点呢？
