Suppression of Tauopathy by Lysosomal Activation

描述（由申请方提供）：在老化过程中，蛋白质降解速率降低，这种效应可能导致细胞毒性蛋白质的蓄积。这一观察结果表明，在阿尔茨海默病和其他tau蛋白病中，缠结（这些疾病的病理学标志）的存在可能是由于细胞蛋白质质量控制系统对异常tau蛋白的清除受损。虽然认为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）。自噬是一个高度调节的过程，涉及在真核系统中通过溶酶体/空泡系统大量降解长寿命的细胞质大分子和细胞器结构，而UPS选择性降解大多数短寿命的细胞蛋白。虽然现有的关于tau蛋白周转的出版物表明这种蛋白通过UPS被消除，但我们已经确定自噬介导的降解是处理tau蛋白的主要途径。此外，我们已经发现，通过用一类耐受性良好的血脑屏障渗透剂化合物处理来上调溶酶体酶导致突变tau蛋白的高度显著减少。总之，这些数据表明，直接靶向溶酶体降解途径的化合物在治疗tau蛋白病中可能是重要的。该提案将（1）表征溶酶体和自噬途径的扰动是否可以影响正常和聚集倾向形式的tau的运输和降解;（2）确定自噬途径的阻断是否损害诱导型tau转基因小鼠中空间记忆的恢复，以及（3）确定溶酶体活化是否保护tau转基因小鼠免受神经变性。这项R21资助提案代表了一个新的方向，旨在揭示tau蛋白降解的机制，并可能为治疗tau蛋白病和其他神经退行性疾病提供新的工具。

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.