The hsp90 Cochaperone FKBP51 Regulates tau Structure and Function

 描述（由申请人提供）：最近的证据表明，微管相关蛋白tau的中间寡聚体在tau蛋白病中比密集堆积的折叠纤维更具神经毒性。然而，这仍然未经证实，因为缺乏捕获tau聚集体的不同组装的相关机制。在这里，我们将填补这些空白，在我们的知识，通过使用热休克蛋白90/共分子伴侣机制来控制tau结构和组装，以证明如何tau聚集体结构与其毒性。我们的团队表明tau与伴侣Hsp 90物理相互作用，提供了与Hsp 90复合的客户端的第一个三维结构。虽然Hsp 90水平在衰老的大脑中基本上是静态的，但一组可以通过Hsp 90与tau相互作用的辅助分子则更具动态性;在一生中，一些上升，另一些下降。我们发现Hsp 90和一种新兴的辅伴侣，顺式/反式肽基脯氨酰异构酶（PPIase）FK 506结合蛋白51（FKBP 51），通过减少tau β-折叠淀粉样变性来协调引发tau发病机制。这与tau转基因小鼠中寡聚化和神经毒性增加相对应。因此，我们推测Hsp 90复合物控制tau聚集成毒性或良性物质，这取决于相关的辅分子伴侣。事实上，我们现在有证据表明，就像FKBP 51水平在衰老的大脑中增加一样，第二种与Hsp 90相关的PPIase，亲环素40（CyP 40/PPID）的水平也在增加，甚至比FKBP 51更大。就像FKBP 51一样，CyP 40减少tau聚集并产生无定形中间体。现在，我们还发现另外两种辅助分子伴侣，Aha 1和FKBP 52，它们在衰老的大脑中减少，实际上增强了tau蛋白的折叠倾向。有了这些工具，我们现在可以测试的假设，tau毒性产生由于结构变化的tau组件所带来的热休克蛋白90/共分子伴侣系统。为了测试这一点，我们将确定促进tau寡聚体形成的Hsp 90/共伴侣复合物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Hsp 90/辅助分子伴侣复合物是否阻止其毒性。最后，我们将确定热休克蛋白90/辅助分子伴侣复合物，有利于tau蛋白淀粉样蛋白或低聚物的生产功能缺陷的小鼠模型中的tau蛋白病的影响。我们预计，我们将确定使用动态Hsp 90复合物调节tau聚集的方法，这将使我们能够找到有毒tau中间体的结构。我们还将确定不同的Hsp 90/共分子伴侣复合物是否可以对大脑中的异常tau进行差异分类，这可能使我们能够提高针对这种机制的治疗方法的特异性。

 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.