Modulating Hsp70-dependent proteostasis in Alzheimer's Disease

细胞蛋白质的折叠效率低下，蛋白质折叠问题更是 当细胞老化并遇到压力条件时会出现问题。错误折叠的浓度 蛋白质在非复制细胞（如神经元）中甚至进一步升高。因此不 令人惊讶的是，最常见的“蛋白质构象疾病”与 神经变性，其中之一是阿尔茨海默病（AD）。AD的例子是 淀粉样斑块和神经纤维缠结的积累，这分别是由于抗体 和tau。尽管淀粉样蛋白假说和聚集的tau蛋白的细胞效应是不确定的， 有争议的是，蛋白质稳态-或“蛋白质稳态”-在AD神经元中明显受损。 因此，如果可以减轻与Ab和tau积累相关的毒性， 可以减轻AD的悲惨后果和经济负担。幸运的是， 克服压力反应，可以纠正错误折叠的积累引起的毒性， proteins.在应激下诱导的一种保护因子是Hsp 70分子伴侣。Hsp70 结合并保持错误折叠的、易于聚集的蛋白质的溶解性。此外， Hsp 70的水平可以保护细胞免受受损的蛋白质稳态。不幸的是，虽然更高 Hsp 70的水平是暂时的保护，Hsp 70水平的持续增加是有毒的， 需要基因操作，目前还不能用于人类。相反，如果A 化合物可以直接增加Hsp 70分子伴侣的活性而不改变其水平， AD神经元的存活率的改善可能是显而易见的。2008年，一个一流的化合物， 选择性激活Hsp 70功能。NMR分析确定了专属性， 化合物的作用机制。此外，这种Hsp 70激活剂降低了α- 引起帕金森病的突触核蛋白，以及一种易于聚集的多肽 与亨廷顿氏病有关。这些努力来自于 PI和药物发现和药物化学专家，独立于PI GMS的父母资助，而不是专注于一个特定的蛋白质抑制途径。的目标 目前的项目是：（1）合成和表征更多的现有药物的类药物衍生物， Hsp 70分子伴侣激活剂;（2）筛选并建立铅的作用机制 这些化合物在细胞测定中重现了与AD相关的蛋白毒性作用。到 促进进展，当地AD专家将担任项目顾问，并最终成为临床前领导者 将鉴定化合物用于随后的体内研究。

The folding of cellular proteins is inefficient, and the protein folding problem is even more problematic as cells age and encounter stressful conditions. The concentration of misfolded proteins rises even further in non-replicative cells, such as neurons. Therefore, it is not surprising that the most common “protein conformational diseases” are linked to neurodegeneration, one of which is Alzheimer’s Disease (AD). AD is exemplified by the accumulation of amyloid plaques and neurofibrillary tangles, which are respectively due to Ab and tau. Although the amyloid hypothesis and the cellular effects of aggregated tau are controversial, protein homeostasis—or “proteostasis”—is clearly compromised in AD neurons. Therefore, if the toxicity associated with the accumulation of Ab and tau could be lessened, the tragic consequences and financial burden of AD could be ameliorated. Fortunately, cells surmount a stress response that can rectify toxicity arising from the accumulation of misfolded proteins. One protective factor that is induced under stress is the Hsp70 chaperone. Hsp70 binds and maintains the solubility of misfolded, aggregation-prone proteins. In addition, higher levels of Hsp70 can protect cells from compromised proteostasis. Unfortunately, while higher levels of Hsp70 are temporarily protective, a sustained increase in Hsp70 levels is toxic or requires genetic manipulations that cannot currently be administered to humans. In contrast, if a compound could directly increase Hsp70 chaperone activity without changing its levels, then improved survival of AD neurons might be evident. In 2008, a first-in-class compound that selectively activates Hsp70 function was identified. NMR analysis established the specificity and mechanism of action of the compound. Moreover, this Hsp70 activator reduces toxic levels of a- synuclein, which gives rise to Parkinson’s Disease, as well as an aggregation-prone polypeptide associated with Huntington’s disease. These efforts emerged from a collaboration between the PI and an expert in drug discovery and medicinal chemistry and were independent of the PI’s parent grant from GMS, which focuses instead on a specific proteostatic pathway. The goal of the current project is to: (1) synthesize and characterize more drug-like derivatives of existing Hsp70 chaperone activators, and (2) screen and then establish the mechanism of action of lead compounds in cellular assays that recapitulate the proteotoxic effects associated with AD. To catalyze progress, local AD experts will act as project consultants, and ultimately preclinical lead compounds will be identified for subsequent in vivo studies.