The hsp90 Cochaperone FKBP51 Regulates tau Structure and Function

 描述(申请人提供)：最近的证据表明，微管相关蛋白tau的中间寡聚体在tauopy病中比密集堆积的-Sheet纤维具有更大的神经毒性。然而，这一点仍然没有得到证实，因为缺乏相关的机制来捕获不同的tau聚集体。在这里，我们将通过使用Hsp90/辅助伴侣机制来控制tau的结构和组装来填补我们知识中的这些空白，以证明tau的聚集结构如何与其毒性相关。我们的团队证明了tau与伴侣Hsp90在物理上相互作用，提供了客户与Hsp90复合的第一个三维结构。虽然在老化的大脑中，Hsp90的水平基本上是静态的，但一组可以通过Hsp90与tau结合的辅助伴侣要动态得多；一些在一生中上升，另一些在一生中下降。我们发现HSP90和上升的辅助伴侣之一，顺式/反式肽基-脯氨酰异构酶(PPIase)FK506结合蛋白51(FKBP51)协同作用，通过减少tau-Sheet淀粉样变性而引发tau的发病。这与tau转基因小鼠的寡聚化和神经毒性增加相对应。因此，我们推测Hsp90复合体控制tau聚集成有毒或良性物种取决于相关的辅助伴侣。事实上，我们现在有证据表明，就像FKBP51水平在老化的大脑中增加一样，另一种与Hsp90相关的PPIase-亲环素40(CyP40/PPID)的水平也在增加，甚至比FKBP51的水平更高。就像FKBP51一样，CyP40减少了tau的聚集，产生了无定形的中间产物。现在，我们还发现另外两个辅助伴侣，AHA1和FKBP52，它们在老化的大脑中减少，实际上增强了tau的-Sheet倾向。有了这些工具，我们现在可以检验这样的假设，即tau毒性是由于Hsp90/辅助伴侣系统导致tau组装的结构变化而产生的。为了测试这一点，我们将确定促进tau齐聚物形成的Hsp90/共伴侣复合体是否不可避免地导致毒性。然后，我们将确定刺激tau淀粉样变性的Hsp90/辅助伴侣复合体是否可以防止其毒性。最后，我们将确定有利于tau淀粉样蛋白或寡聚体产生的Hsp90/辅助伴侣复合体对tau病小鼠模型中功能缺陷的影响。我们预计我们将找到利用动态Hsp90复合体来调控tau聚集的方法，这将使我们能够深入了解有毒tau中间体的结构。我们还将确定不同的Hsp90/辅助伴侣复合体是否可以区分大脑中异常的tau，可能允许我们提高针对这一机制的治疗的特异性。

 DESCRIPTION (provided by applicant): Recent evidence suggests that intermediate oligomers of the microtubule-associated protein tau are more neurotoxic in tauopathies than densely packed -sheet fibrils. However, this remains unproven because relevant mechanisms to trap distinct assemblies of tau aggregates have been lacking. Here we will fill these gaps in our knowledge by using the Hsp90/co-chaperone machinery to control tau structure and assembly to prove how tau aggregate structure relates to its toxicity. Our team showed that tau physically interacts with the chaperone Hsp90, providing the first 3-dimensional structure of a client complexed with Hsp90. While Hsp90 levels are largely static in the aging brain, a group of co-chaperones that can interface with tau through Hsp90 are much more dynamic; some rise and others fall during a lifetime. We have found that Hsp90 and one of the rising co-chaperones, the cis/trans peptidyl-prolyl isomerase (PPIase) FK506 binding protein 51 (FKBP51), coordinate to provoke tau pathogenesis by reducing tau -sheet amyloidosis. This corresponded with increased oligomerization and neurotoxicity in tau transgenic mice. Thus, we speculate that the Hsp90 complex controls whether tau aggregates into toxic or benign species depending on the associated co- chaperones. In fact, we now have evidence that just as FKBP51 levels increase in the aging brain, so do the levels of a second Hsp90-associated PPIase, cyclophilin 40 (CyP40/PPID), to an even greater extent than FKBP51. And just like FKBP51, CyP40 reduces tau aggregation and produces amorphous intermediates. Now, we have also discovered that two other co-chaperones, Aha1 and FKBP52, which decrease in the aging brain, actually enhance the -sheet propensity of tau. With these tools, we can now test the hypothesis that tau toxicity arises due to structural changes in tau assemblies brought on by the Hsp90/co-chaperone system. To test this, we will determine if Hsp90/co-chaperone complexes that promote tau oligomer formation inevitably lead to toxicity. We will then determine if Hsp90/co-chaperone complexes that stimulate tau amyloidosis prevent its toxicity. Lastly we will determine the impact of Hsp90/co-chaperone complexes that favor tau amyloid or oligomer production on functional deficits in a mouse model of tauopathy. We anticipate that we will identify ways to regulate tau aggregation using the dynamic Hsp90 complex, which will allow us to home in on structures of toxic tau intermediates. We also will determine whether distinct Hsp90/co-chaperone complexes can differentially triage aberrant tau in the brain, possibly allowing us to improve the specificity of therapeutics targeting this mechanism.