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The hsp90 Cochaperone FKBP51 Regulates tau Structure and Function

hsp90 Cochaperone FKBP51 调节 tau 结构和功能

基本信息

批准号：
9272217
负责人：
Chad A. Dickey
金额：
$ 2.79万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-22 至 2019-08-21
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9272217
关键词：
Amyloid Amyloidosis Behavioral Benign Biochemical Brain Cells Cellular Assay Client Cognitive deficits Complex Coupled Cyclophilins Data 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 chaperone machinery clinical investigation cyclophilin D drug development falls improved in vivo light scattering mouse model nervous system disorder neuron loss neurotoxic neurotoxicity prevent public health relevance response tacrolimus binding protein 4 tau Proteins tau aggregation tau mutation therapeutic target three dimensional structure tool

项目摘要

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.