Suppression of Tauopathy by Lysosomal Activation

描述(申请人提供)：在老化过程中，蛋白质降解率下降，这种影响可能有助于细胞毒性蛋白质的积累。这一观察结果表明，在阿尔茨海默病和其他tau病中，缠结(这些疾病的病理标志)的存在可能是由于细胞蛋白质质量控制系统对异常tau的清除受到损害。虽然人们认为tau在这些疾病中的积累是翻译后修饰的产物，但关于tau降解过程的具体信息很少。在真核生物中，降解蛋白质的主要质量控制系统是自噬途径和泛素-蛋白酶体系统(UPS)。自噬是一个高度调控的过程，涉及到真核系统中长寿命的细胞质大分子和细胞器结构通过溶酶体/空泡系统的大量降解，而UPS选择性地降解大多数短暂的细胞蛋白。虽然现有的关于tau周转的文献表明，这种蛋白质是通过UPS消除的，但我们已经确定自噬介导的降解是tau蛋白处置的主要途径。此外，我们还发现，一类耐受性良好的血脑屏障穿透性化合物处理后，溶酶体酶的上调导致突变的tau蛋白显著减少。综上所述，这些数据表明，直接针对溶酶体降解途径的化合物在治疗复发性疾病方面具有潜在的重要意义。这一建议将(1)表征溶酶体和自噬途径的扰动是否可以影响正常形式和易于聚集的tau形式的运输和降解；(2)确定阻断自噬途径是否会损害可诱导的tau转基因小鼠的空间记忆恢复；(3)确定溶酶体激活是否可以防止tau转基因小鼠的神经退化。这项R21拨款提案代表了解开tau蛋白降解机制的努力的一个新方向，并可能导致治疗tau病和其他神经退行性疾病的新工具。

DESCRIPTION (provided by applicant): During the aging process, rates of protein degradation decrease, and this effect can contribute to the accumulation of cytotoxic proteins. This observation suggests that in Alzheimer's disease and other tauopathies the presence of tangles (a pathological hallmark of these diseases) may be due to the impaired clearance of abnormal tau by cellular protein quality control systems. While it is believed that the accumulation of tau in these diseases is the product of posttranslational modifications, little information is specifically available about the degradation processes of tau. In eukaryotes, the major quality control systems that degrade proteins are the autophagy pathway and the ubiquitin-proteasome system (UPS). Autophagy is a highly regulated process that involves the bulk degradation of long-lived cytoplasmic macromolecules and organelle structures in the eukaryotic systems through the lysosomal/vacuolar system, whereas the UPS selectively degrades a majority of short-lived cellular proteins. While existing publications on tau turnover have suggested that this protein is eliminated through the UPS, we have identified autophagy-mediated degradation as a major route for disposal of tau protein. Furthermore, we have found that the upregulation of lysosomal enzymes by treatment with a class of well-tolerated, blood-brain-barrier penetrant compounds results in a highly significant reduction of mutant tau protein. Taken together, this data shows that compounds that directly target lysosomal degradation pathways are potentially important in the treatment of tauopathies. This proposal will (1) characterize whether perturbations of the lysosomal and autophagy pathways can affect the trafficking and degradation of both normal and aggregation-prone forms of tau; (2) determine if blockade of the autophagy pathway impairs recovery of spatial memory in inducible tau transgenic mice, and (3) determine if lysosomal activation protects against neurodegeneration in tau transgenic mice. This R21 grant proposal represents a novel direction in the effort to unravel the mechanisms governing the degradation of tau protein and may lead to new tools for the treatment of tauopathies and other neurodegenerative diseases.