The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins
The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins
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DOI：
10.1172/jci29715
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发表时间：
2007-03-01
影响因子：
15.9
通讯作者：
Petrucelli, Leonard
中科院分区：
文献类型：
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作者：
Dickey, Chad A.;Kamal, Adeela;Petrucelli, Leonard
阿尔茨海默病(AD)的一个主要病理成分是由过度磷酸化的tau(p-tau)组成的神经纤维缠结的形成。加快清除这些p-tau物种可能是一种相关的治疗策略。在这里，我们报告，抑制Hsp90导致p-tau水平下降，而不依赖于热休克因子1(HSF1)的激活。Hsp70相互作用蛋白的羧基末端是一种tau泛素连接酶，是这一机制的关键介体。Cochaperone也参与了Hsp90介导的p-tau的去除，而成熟的Hsp90复性复合体的作用则阻止了这一作用。这是我们所知的第一次证明了阻断折叠途径通过降解促进了p-tau的周转。我们还表明，外周给药一种新型的Hsp90抑制剂促进了在tau病小鼠模型中p-tau物种的选择性减少，进一步表明Hsp90复合体在tau病的发病机制中起着中心作用。在已知AD大脑受影响区域的高亲和力Hsp90复合体的背景下，这些数据暗示Hsp90在AD和其他自发性疾病的发展中发挥核心作用，并可能为开发基于Hsp90的新的治疗策略提供理论基础。
A primary pathologic component of Alzheimer's disease (AD) is the formation of neurofibrillary tangles composed of hyperphosphorylated tau (p-tau). Expediting the removal of these p-tau species may be a relevant therapeutic strategy. Here we report that inhibition of Hsp90 led to decreases in p-tau levels independent of heat shock factor 1 (HSF1) activation. A critical mediator of this mechanism was carboxy terminus of Hsp70-interacting protein (CHIP), a tau ubiquitin ligase. Cochaperones were also involved in Hsp90-mediated removal of p-tau, while those of the mature Hsp90 refolding complex prevented this effect. This is the first demonstration to our knowledge that blockade of the refolding pathway promotes p-tau turnover through degradation. We also show that peripheral administration of a novel Hsp90 inhibitor promoted selective decreases in p-tau species in a mouse model of tauopathy, further suggesting a central role for the Hsp90 complex in the pathogenesis of tauopathies. When taken in the context of known high-affinity Hsp90 complexes in affected regions of the AD brain, these data implicate a central role for Hsp90 in the development of AD and other tauopathies and may provide a rationale for the development of novel Hsp90-based therapeutic strategies.