Chaperones increase association of tau protein with microtubules
Chaperones increase association of tau protein with microtubules
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DOI：
10.1073/pnas.242720499
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发表时间：
2003-01-21
影响因子：
11.1
通讯作者：
Xu, HX
中科院分区：
文献类型：
--
作者：
Dou, F;Netzer, WJ;Xu, HX
分子伴侣及其在蛋白质折叠中的功能与几种神经退行性疾病有关，包括帕金森病和亨廷顿病，其特征在于蛋白质聚集体（例如，分别为α-突触核蛋白和亨廷顿蛋白）。这些聚集体已经在各种实验系统中显示出对分子伴侣水平的变化的响应，这表明治疗干预的可能性和伴侣在疾病发病机制中的作用。目前尚不清楚伴侣蛋白是否也在阿尔茨海默病中发挥作用，阿尔茨海默病是一种以β-淀粉样蛋白和tau蛋白聚集为特征的神经退行性疾病。在这里，我们报告了聚集的tau蛋白和热休克蛋白（Hsp）70/90在tau转基因小鼠和阿尔茨海默病的大脑水平之间的反比关系。在各种细胞模型中，增加的Hsp 70和Hsp 90水平促进tau溶解性和tau与微管的结合，减少不溶性tau并导致tau磷酸化减少。相反，降低Hsp 70和Hsp 90的水平导致相反的效果。我们还证明了分子伴侣与tau蛋白的直接关联。我们的研究结果表明，分子伴侣的上调可能会抑制形成神经元缠结的分区到一个生产性的折叠通路，从而防止tau蛋白聚集。
Molecular chaperones and their functions in protein folding have been implicated in several neurodegenerative diseases, including Parkinson's disease and Huntington's disease, which are characterized by accumulation of protein aggregates (e.g., alpha-synuclein and huntingtin, respectively). These aggregates have been shown in various experimental systems to respond to changes in levels of molecular chaperones suggesting the possibility of therapeutic intervention and a role for chaperones in disease pathogenesis. It remains unclear whether chaperones also play a role in Alzheimer's disease, a neurodegenerative disorder characterized by beta-amyloid and tau protein aggregates. Here, we report an inverse relationship between aggregated tau and the levels of heat shock protein (Hsp)70/90 in tau transgenic mouse and Alzheimer's disease brains. In various cellular models, increased levels of Hsp70 and Hsp90 promote tau solubility and tau binding to microtubules, reduce insoluble tau and cause reduced tau phosphorylation. Conversely, lowered levels of Hsp70 and Hsp90 result in the opposite effects. We have also demonstrated a direct association of the chaperones with tau proteins. Our results suggest that up-regulation of molecular chaperones may suppress formation of neurofibrillary tangles by partitioning tau into a productive folding pathway and thereby preventing tau aggregation.