PROTEASOMAL IMPAIRMENT AND ENHANCED TOXICITY OF PROTEIN AGGREGATES

描述(申请人提供)：蛋白质错误折叠和异常聚合与许多神经退行性疾病有关，包括阿尔茨海默病、帕金森氏病、亨廷顿病和普恩病毒病。这些蛋白质构象紊乱的零星形式往往比遗传性疾病更为普遍。要了解这种散发性疾病是如何发生的，可能需要阐明有助于蛋白质聚集的其他遗传和环境因素。在这个试点项目中提出的研究将解决一个额外的因素，泛素-蛋白酶体系统和蛋白质聚集之间的因果关系。蛋白酶体活性、蛋白质聚集和疾病之间的因果关系一直很难辨别，部分原因是同时出现了细胞毒性。我们利用酵母中具有良好特性的蛋白聚集体作为进一步研究在细胞中有毒或无毒的蛋白质聚集体的模型。我们发现，与阿尔茨海默病相关的泛素突变形式的表达增强了普恩蛋白聚集体的毒性。这项建议中使用的模型系统为快速筛选调节细胞对蛋白酶体损伤和有毒蛋白聚集体反应的因素提供了新的策略。在这项先导研究中，我们将确定细胞的改变，以减轻突变泛素表达的影响。这项研究的未来方向可能会为阿尔茨海默病的治疗开辟新的途径。与公共健康相关：蛋白质需要在特定的三维结构中正确折叠，才能发挥全部功能。蛋白质不能保持适当的折叠是导致人类几种毁灭性疾病的原因。我们正在研究蛋白质稳态的变化，特别是蛋白质降解机制的变化，如何影响蛋白质的错误折叠和聚集。我们正在使用一种新的遗传系统，以确定如何在细胞中纠正这些问题。

DESCRIPTION (provided by applicant): Protein misfolding and aberrant polymerization have been implicated in many neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and prion diseases. Sporadic forms of these protein conformational disorders are often much more prevalent than inherited forms of the diseases. Understanding how the sporadic disease is initiated may require elucidating other genetic and environmental factors that contribute to protein aggregation. The research proposed in this pilot project will address the causal relationship between one additional factor, the ubiquitin-proteasome system, and protein aggregation. The causal relationship between proteasomal activity, protein aggregation, and disease has been difficult to discern partially due to the concurrent appearance of cellular toxicity. We have employed the well-characterized prion protein aggregates in yeast as a model for further investigation of protein aggregates that can be toxic or non-toxic in cells. We have found that expression of a mutant form of ubiquitin associated with Alzheimer's disease enhances the toxicity of prion protein aggregates. The model system used in this proposal provides novel strategies for rapid screening of factors that modulate the cellular response to proteasomal impairment and toxic protein aggregates. In this pilot study we will identify cellular alterations that alleviate the effects of mutant ubiquitin expression. Future directions of this research may lead to new therapeutic avenues for Alzheimer's disease. PUBLIC HEALTH RELEVANCE: Proteins need to be properly folded in a particular three dimensional structure for full functionality. The inability of proteins to maintain proper folding is the cause of several devastating human diseases. We are investigating how changes in the protein homeostasis, specifically in the protein degradation machinery, impact protein misfolding and aggregation. We are using a novel genetic system in order to determine how these problems can be corrected in the cell.