Jinwal Umesh K, Koren John, O'Leary John C, Jones Jeffrey R, Abisambra Jose F, Dickey Chad A
Department of Molecular Medicine, Byrd Alzheimer's Institute, University of South Florida, Tampa, Florida.
Mol Cell Pharmacol. 2010 Jan 1;2(2):43-46.
Neurodegenerative diseases caused by abnormal accumulation of the microtubule associated protein tau (MAPT, tau) are collectively called tauopathies. The most devastating tau related disorder is Alzheimer's disease (AD). Molecular chaperones such as heat shock proteins (Hsp) have emerged as critical regulators of tau stability. Several studies from our group and others have shown that the chaperone network can be targeted for the development of therapeutic strategies for AD and other neurodegenerative diseases. Here we will discuss a recent paper and current work from our laboratory where we have manipulated the ATPase activity of the 70-kDa heat shock protein (Hsp70) to regulate tau turnover. A high-throughput screening assay revealed several compounds that activated or inhibited Hsp70's ATPase activity. Inhibitors dramatically and rapidly reduced tau levels, whereas activators stabilized tau, both in cells and brain tissue. Moreover, increased levels of Hsp70 improved ATPase inhibitor efficacy, suggesting that therapies aimed at inducing Hsp70 levels followed by inhibition of its ATPase activity may be a very effective strategy to treat AD. These findings demonstrate that Hsp70 ATPase activity can be targeted to modify the pathologies of AD and other tauopathies.
由微管相关蛋白tau（MAPT，tau）异常积聚引起的神经退行性疾病统称为tau蛋白病。最具破坏性的与tau相关的疾病是阿尔茨海默病（AD）。诸如热休克蛋白（Hsp）等分子伴侣已成为tau稳定性的关键调节因子。我们小组和其他团队的多项研究表明，伴侣蛋白网络可作为开发AD和其他神经退行性疾病治疗策略的靶点。在此，我们将讨论最近一篇论文以及我们实验室目前的工作，在这些研究中，我们操纵了70 kDa热休克蛋白（Hsp70）的ATP酶活性来调节tau的周转。一项高通量筛选试验发现了几种激活或抑制Hsp70 ATP酶活性的化合物。在细胞和脑组织中，抑制剂显著且迅速地降低了tau水平，而激活剂则稳定了tau。此外，Hsp70水平的升高提高了ATP酶抑制剂的疗效，这表明旨在提高Hsp70水平然后抑制其ATP酶活性的疗法可能是治疗AD的一种非常有效的策略。这些发现表明，Hsp70的ATP酶活性可作为改变AD和其他tau蛋白病病理的靶点。
