Amyloid elimination by Hsp104 and substrate-optimized variants

我们迫切需要创新，以对抗几个日益流行的和 致命的神经退行性疾病，包括阿尔茨海默氏症和帕金森氏症 疾病，它贪婪地吞噬我们的社会和经济资源。这些障碍 共享共同的致病机制，在这种机制中，特定的蛋白质错误折叠成共享的 令人惊讶的普通构象，称为淀粉样蛋白。不同蛋白质的淀粉样纤维 采用类似的交叉β结构，其中β-Sheet的链垂直运行 传到纤维轴上。此外，高度细胞毒性低聚物具有独特的非专利 结构经常在纤维之前积累。尽管形成的特定蛋白质 淀粉样蛋白和沉积的精确定位在每种疾病中都不同，这些是共同的 淀粉样蛋白形成的各个方面带来了希望，针对淀粉样蛋白的治疗策略可能 具有广泛的应用前景。然而，淀粉样蛋白的特殊稳定性，包括： 对蛋白酶和十二烷基硫酸钠的抗性，使它们格外难以清除。事实上，他们 被广泛认为是难以处理的。值得注意的是，我们发现一种蛋白质- 酵母中的重塑因子Hsp104可以迅速分解淀粉样纤维和 由酵母Pron蛋白Sup35和Ure2组成的寡聚体。史无前例的 HSP104重塑这些淀粉样蛋白结构的快捷性提高了人们的意识 淀粉样蛋白的构象不是难治性的，而且一种细胞因子能够逆转 淀粉样蛋白的形成已经进化。奇怪的是，尽管细菌在植物中高度保守，但 和真菌，Hsp104已经神秘地从后生动物谱系中消失了。我们假设 HSP104在疾病相关淀粉样蛋白中的应用可能具有广泛的治疗作用 潜力。因此，我们的目标是：(1)消灭淀粉样纤维、低聚物和相关的 利用HSP104研究多种人类疾病相关蛋白的蛋白毒性；(2)工程师 或者进化出底物优化的Hsp104变种，攻击选定的淀粉样蛋白； 以及(3)为动物模型产生Hsp104或底物优化的变体疗法 淀粉样变性疾病。这些研究将为新的方法提供基础 攻克困扰人类的毁灭性的淀粉样变性疾病。

We are in dire need of innovations to combat several increasingly prevalent and inexorably lethal neurodegenerative disorders, including Alzheimer's and Parkinson's disease, which voraciously devour our social and economic resources. These disorders share a common pathogenic mechanism in which specific proteins misfold into a shared surprisingly generic conformation, termed amyloid. Amyloid fibers of diverse proteins adopt a similar `cross-β' structure, in which the strands of the β-sheets run perpendicular to the fiber axis. Further, highly cytotoxic oligomers possessing a distinct generic structure frequently accumulate prior to fibers. Although the specific protein that forms amyloid and precise localization of the deposits varies in each disease, these shared facets of amyloidogenesis bring hope that therapeutic strategies that target amyloid may have broad applications. The exceptional stability of amyloids, however, including: protease- and SDS-resistance, makes them extraordinarily difficult to clear. Indeed, they are widely perceived as intractable. Remarkably, we have found that a protein- remodeling factor from yeast, Hsp104, can rapidly disassemble amyloid fibers and oligomers comprised of the yeast prion proteins, Sup35 and Ure2. The unprecedented alacrity at which Hsp104 remodels these amyloid structures raises awareness that amyloid conformers are not intractable, and that a cellular factor capable of reversing amyloidogenesis has evolved. Curiously, although highly conserved in plants, bacteria and fungi, Hsp104 has been mysteriously lost from metazoan lineages. We hypothesize that application of Hsp104 to disease-associated amyloids may have broad therapeutic potential. Hence, we aim to: (1) annihilate amyloid fibers, oligomers and associated proteotoxicity of diverse human disease-associated proteins using Hsp104; (2) engineer or evolve substrate-optimized Hsp104 variants that attack select amyloidogenic proteins; and (3) generate Hsp104 or substrate-optimized variant therapies for animal models of amyloid-disorders. These studies will provide the foundations for new approaches to attack the devastating amyloid-disorders that plague humankind.