The hsp90 Cochaperone FKBP51 Regulates tau Structure and Function

hsp90 Cochaperone FKBP51 调节 tau 结构和功能

• 批准号: 9204431
• 负责人: David E Kang
• 金额: $ 51.1万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9204431
• 关键词: Amyloid; Amyloidosis; Behavioral; Benign; Biochemical; Brain; Cells; Cellular Assay; Client; Cognitive deficits; Complex; Coupled; Cyclophilins; Data; Drug Targeting; Electron Microscopy; Electrophysiology (science); Home environment; Journals; Knowledge; Lead; MAPT gene; Mediating; Metabolism; Modeling; Molecular; Molecular Chaperones; Mus; NMR Spectroscopy; Nerve Degeneration; Neuronal Dysfunction; Neurosciences; Outcome; Pathogenesis; Peptidylprolyl Isomerase; Phenotype; Production; Proteins; Science; Specificity; Structure; Symptoms; System; Tacrolimus Binding Proteins; Tauopathies; Testing; Toxic effect; Transgenic Mice; Triage; Work; adeno-associated viral vector; aging brain; analytical ultracentrifugation; beta pleated sheet; chaperone machinery; clinical investigation; cyclophilin D; drug development; falls; improved; in vivo; light scattering; mouse model; nervous system disorder; neuron loss; neurotoxic; neurotoxicity; photo switch; prevent; proteotoxicity; public health relevance; response; tacrolimus binding protein 4; tau Proteins; tau aggregation; tau mutation; therapeutic target; three dimensional structure; tool

 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.

 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 病中比密集的 β-片原纤维具有更大的神经毒性。然而，这一点尚未得到证实，因为缺乏捕获不同 tau 聚集体组装的相关机制。在这里，我们将通过使用 Hsp90/共伴侣机制来控制 tau 结构和组装来填补我们的知识空白，以证明 tau 聚集结构与其毒性之间的关系。我们的团队证明 tau 与伴侣 Hsp90 发生物理相互作用，从而提供了与 Hsp90 复合的客户端的第一个 3 维结构。虽然 Hsp90 水平在衰老的大脑中基本上是静态的，但一组可以通过 Hsp90 与 tau 蛋白相互作用的共伴侣则更具动态性。在一生中，有些人会上升，有些人会下降。我们发现 Hsp90 和其中一种新兴的辅助伴侣，顺/反肽基脯氨酰异构酶 (PPIase) FK506 结合蛋白 51 (FKBP51)，通过减少 tau 片淀粉样变性来协调激发 tau 发病机制。这与 tau 转基因小鼠中寡聚化和神经毒性的增加相对应。因此，我们推测 Hsp90 复合物根据相关的共伴侣控制 tau 蛋白是否聚集成有毒或良性物种。事实上，我们现在有证据表明，随着衰老大脑中 FKBP51 水平的增加，第二种 Hsp90 相关 PPI 酶、亲环蛋白 40 (CyP40/PPID) 的水平也会增加，其程度甚至比 FKBP51 还要高。就像 FKBP51 一样，CyP40 减少 tau 聚集并产生无定形中间体。现在，我们还发现另外两个辅助伴侣 Aha1 和 FKBP52（它们在衰老的大脑中减少）实际上增强了 tau 的  片层倾向。借助这些工具，我们现在可以检验以下假设：tau 毒性是由于 Hsp90/共伴侣系统引起的 tau 组装体的结构变化而产生的。为了测试这一点，我们将确定促进 tau 寡聚体形成的 Hsp90/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 Hsp90/共伴侣复合物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/共伴侣复合物对 tau 病小鼠模型功能缺陷的影响。我们预计将找到使用动态 Hsp90 复合物调节 tau 聚集的方法，这将使我们能够深入研究有毒 tau 中间体的结构。我们还将确定不同的 Hsp90/共伴侣复合物是否可以对大脑中的异常 tau 蛋白进行差异分类，这可能使我们能够提高针对该机制的治疗的特异性。