Unique ubiquitin processes in misfolded protein diseases of the nervous system

与年龄相关的神经系统疾病是多种多样的，随着 人口老龄化。到目前为止，他们中最有影响力的人没有得到成功的临床干预；因此，他们的研究构成了神经科学领域的明显需要。其中包括 疾病是阿尔茨海默氏症、帕金森氏症和聚谷氨酰胺家族的疾病，由错误折叠的蛋白质的存在、积累和聚集引起。开创性的工作剖析了如何 细胞协调反应以延迟或抑制错误折叠的蛋白质毒性，然而神经元最终屈服于这些蛋白质和疾病的进展。在参与维持神经元的过程中 面对错误折叠的蛋白质，动态平衡是重折叠和降解的途径。这些问题的关键 过程是一种小修饰蛋白，泛素。在这里，我们试图研究泛素的一个方面 泛素最为人所知的是通过化学作用靶向蛋白酶体降解的底物。 绑在他们身上。泛素存在于多种类型的构型中，包括可以 采用多种拓扑复杂性和长度，并配合下游衬底 识别和处理。在多泛素链的类型中，有未锚定的物种 不会附着在其他蛋白质上。我们最近发表了关于这些链在体内的存在、功能、利用和处理的证据。最耐人寻味的发现之一是观察到自由泛素链可以整体连接到底物上，而不需要是第一个 分解成单体。这一新发现让我们想知道它是否对细胞有益 在压力下使用现成的链条来维持动态平衡。我们在试飞中发现， 游离泛素链抑制致病蛋白的毒性。我们的先导数据引导我们假设，未锚定的多泛素有利于细胞对错误折叠疾病的反应 蛋白质。我们建议通过三个目标来检验这一假设，这三个目标利用了生理和生化分析的组合。

Age-related diseases of the nervous system are diverse and will continue to grow in importance as the population ages. So far, the most impactful among them have eluded successful clinical intervention; therefore, their investigation constitutes a clear need in the field of neuroscience. Among these diseases are Alzheimer's, Parkinson's and the polyglutamine family of disorders, caused by the presence, accumulation and aggregation of misfolded proteins. Ground-breaking work has dissected how cells coordinate responses to delay or suppress misfolded protein toxicity, yet neurons ultimately succumb to these proteins and diseases progress. Among processes involved in maintaining neuronal homeostasis in the face of misfolded proteins are refolding and degradation pathways. Key to these processes is the small modifier protein, ubiquitin. Here, we seek to investigate an aspect of ubiquitin that has eluded exploration in neurodegeneration: unanchored, or free, ubiquitin chains and their impact on misfolded protein toxicity. Ubiquitin is best known for targeting substrates for proteasomal degradation by being chemically tethered onto them. Ubiquitin exists in numerous types of configurations, including chains that can adopt a wide array of topological complexities and length, and that coordinate downstream substrate recognition and processing. Among the types of poly-ubiquitin chains are unanchored species that are not attached onto other proteins. We recently published evidence on the presence, function, utilization and processing of these chains in vivo. Among the most intriguing findings was the observation that free ubiquitin chains can be conjugated onto substrates en bloc, without the need to be first dismantled into monomers. This novel finding led us to wonder whether it may be beneficial for cells under stress to use ready-made chains to maintain homeostasis. In pilot examinations we found that free ubiquitin chains suppress toxicity from disease-causing proteins. Our pilot data lead us to hypothesize that unanchored poly-ubiquitin is beneficial to the cellular response to misfolded disease proteins. We propose to test this hypothesis through three aims that utilize a combination of physiological and biochemical assays.