Modulating Hsp70-dependent proteostasis in Alzheimer's Disease

细胞蛋白质的折叠效率很低，蛋白质折叠问题就更严重了 随着细胞老化和遇到压力条件，这是有问题的。错误折叠的浓度 在非复制性细胞中，如神经元，蛋白质的含量甚至会进一步上升。因此，它不是 令人惊讶的是，最常见的“蛋白质构象疾病”与 神经退行性变，其中之一是阿尔茨海默病(AD)。广告的例证是 分别由抗体引起的淀粉样斑块和神经原纤维缠结的堆积 还有陶。尽管淀粉样蛋白假说和聚集的tau的细胞效应是 有争议的是，蛋白质稳态--或“蛋白质稳态”--在阿尔茨海默病神经元中明显受到损害。 因此，如果与抗体和tau积累相关的毒性能够减少，那么 AD的悲剧性后果和经济负担可以得到改善。幸运的是，细胞 克服压力反应，可以纠正因错误折叠积累而产生的毒性 蛋白质。在压力下诱导的一个保护性因素是Hsp70伴侣。热休克蛋白70 结合并维持错误折叠的、易于聚集的蛋白质的溶解性。此外，更高的 热休克蛋白70的水平可以保护细胞免受蛋白质平衡的损害。不幸的是，虽然更高 Hsp70水平是暂时的保护性的，Hsp70水平的持续上升是有毒的或 需要进行目前不能对人类实施的基因操作。相反，如果一个 化合物可以在不改变其水平的情况下直接增加Hsp70的伴侣活性，然后 AD神经元存活率的改善可能是显而易见的。2008年，一家一流的化合物 选择性激活Hsp70功能已被鉴定。核磁共振分析证实了其特异性和 该化合物的作用机理。此外，这种Hsp70激活剂可降低a- 导致帕金森氏症的突触核蛋白以及一种易于聚集的多肽 与亨廷顿氏症有关。这些努力来自于 PI和药物发现和药物化学方面的专家，独立于PI 来自GMS的父母资助，而不是专注于一种特定的蛋白抑制途径。的目标是 目前的工作是：(1)合成和表征更多的已有的类似药物的衍生物 HSP70分子伴侣激活剂；(2)筛选并建立铅的作用机制 细胞分析中概括与阿尔茨海默病相关的蛋白毒性效应的化合物。至 推动进展，当地AD专家将担任项目顾问，并最终领导临床前工作 化合物将被确定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.