Optimizing and defining the mechanism of alpha-synuclein disaggregation by Hsp104

描述(申请人提供)：蛋白质？-突触核蛋白(？-syn)的错误折叠和聚集与帕金森病(PD)有关，帕金森病是一种毁灭性的神经退行性运动障碍。在帕金森病患者中，β-syn错误折叠成一种异常的蛋白质构象，称为淀粉样蛋白，高度稳定，具有特征的交叉？？结构，而且在很大程度上被认为是一种棘手的疾病。有证据表明，β-SYN的淀粉样蛋白前体寡聚体比纤维本身具有更大的毒性。此外，某些罕见的？-syn突变与家族性帕金森病有关，通常会导致发病年龄降低和症状严重程度增加。这些突变体已被证明增加了？-SYN聚集的倾向或增加了淀粉样蛋白前体低聚物的浓度。一种显著的酵母蛋白，Hsp104，已被证明通过解聚？-syn纤维和低聚体来改善？-syn聚集的症状。然而，需要高浓度的Hsp104来观察解聚，这降低了这种潜在的PD治疗的有效性。此外，尚不清楚Hsp104是如何改造？-SYN纤维的。 以及寡聚体，这掩盖了这种蛋白质可能被进一步开发来治疗帕金森病的方法。我们已经分离出一种对β-SYN纤维具有更强效力的HSP104突变体，这给了我们信心，HSP104最终将成为一种可行的PD治疗方法。这项建议的目标是优化HSP104，以获得更高的抗？-SYN纤维和低聚物活性。我们计划同时针对野生型和疾病相关的突变体？-syn，以确保Hsp104可以用于治疗所有帕金森病病例。我们还旨在了解hsp104对？-syn纤维和寡聚体的解聚机制，以便进一步优化hsp104作为帕金森病的治疗药物。

DESCRIPTION (provided by applicant): Misfolding and aggregation of the protein ?-synuclein (? -syn) is associated with Parkinson's Disease (PD), which is a devastating neurodegenerative movement disorder. In PD, ? -syn misfolds into an aberrant protein conformation, termed amyloid, which is highly stable, possesses a characteristic cross-?? structure, and is largely viewed to be an intractable condition. There is evidence that pre- amyloid oligomers of ? -syn possess greater toxicity than the fibers themselves. Furthermore, certain rare mutations of ? -syn are associated with familial forms of PD and often result in a decreased age of onset and increased severity of symptoms. These mutants have been shown to increase propensity of ? -syn aggregation or to increase the concentration of the pre-amyloid oligomers. A remarkable yeast protein, Hsp104, has been shown to ameliorate symptoms of ? -syn aggregation in a rat model of PD by disaggregating the ? -syn fibers and oligomers. However, high concentrations of Hsp104 were required to observe disaggregation, which reduces the effectiveness of this potential PD therapeutic. Additionally, it is not clear how Hsp104 is able to remodel ? -syn fibers and oligomers, which obscures ways in which this protein may be further developed to treat PD. We have isolated an Hsp104 mutant with even greater potency towards ? -syn fibers, which gives us confidence that Hsp104 will be eventually become a viable PD treatment. The goal of this proposal is to optimize Hsp104 for even higher anti-?? -syn fiber and oligomer activity. We plan on targeting both wild-type and disease associated mutants of ? -syn to ensure that Hsp104 can be used to treat all cases of PD. We also aim to understand the mechanism of Hsp104 disaggregation of ? -syn fibers and oligomers in order to facilitate even further optimization of Hsp104 as a PD therapeutic.