(Download) "Triggers and Enhancers of Tau Aggregation" by Haishan Yin ~ Book PDF Kindle ePub Free
eBook details
- Title: Triggers and Enhancers of Tau Aggregation
- Author : Haishan Yin
- Release Date : January 18, 2013
- Genre: Medical,Books,Professional & Technical,
- Pages : * pages
- Size : 18687 KB
Description
Alzheimer's disease is characterized in part by the aggregation of tau protein into filamentous inclusions. Tau aggregation is not only a robust marker of disease progression, but also contributes directly to degeneration in affected neurons. In this context, the mechanism of tau filament formation and its modulation by posttranslational modification are of fundamental importance. To clarify the forces that drive neurofibrillary lesion formation, the mechanism of tau filament formation is investigated in vitro and in cellular models. First, we clarify that the aggregation reaction is triggered by environmental conditions that stabilize assembly-competent conformations. It also shows that planar aromatic dyes capable of binding the intermediate state with high affinity are also capable of triggering fibrillization. Dye-mediated tau aggregation is characterized in detail and demonstrated as a novel approach to study tau aggregation mechanism in vitro. Using one of these small molecule dyes as inducer, role of proteolytic post-translational modification on tau aggregation is studied. The data show that C-terminal proteolysis can modulate tau filament accumulation through decreasing critical concentration and also through directly augmenting the efficiency of the nucleation reaction. Similarly, Congo Red, another planar aromatic dye identified in above experiment, is applied to tau stable cell line to establish a new cell culture model of tauopathy. Formation of detergent insoluble aggregates is both time and agonist concentration dependent without relating to tau hyperphosphorylation. Results also suggest that conformational changes associated with aggregation are incompatible with microtubule binding, and that aggregation can be toxic in the presence of cellular stress that compromises proteasome function. Tau hyperphosphorylation precedes neuritic lesion formation in Alzheimer's disease, suggesting it participates in the tau fibrillization reaction pathway. Candidate tau protein kinases include casein kinase 1 (CK1) family, which highly overexpress in Alzheimer's disease brain and colocalize with neuritic and granulovacuolar lesions. Here we show that Ckidelta phosphorylates tau in vivo. Next, we demonstrate that dysbindin structural homologue CK1BP is an isoform-selective binding partner of human casein kinase-1 and that the acidic domain of dysbindin and its paralogs in humans may function to recruit CK1 isoforms to protein complexes involved in multiple biological functions.
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