Misfolded proteins alter the folding capacity of cells

描述（由申请人提供）：拟议的研究旨在定义各种疾病相关聚集倾向蛋白质表现出的蛋白毒性的共同机制，并了解分子伴侣和应激信号通路在调节这种蛋白毒性挑战的折叠稳态中的作用。具体而言，它解决了以下假设：易聚集蛋白的表达影响其他细胞蛋白的折叠，这种效应是由伴侣蛋白网络和应激信号通路介导的，并且细胞折叠能力的下降是与年龄相关的蛋白质折叠疾病恶化的基础。初步数据支持这一主张，表明聚谷氨酰胺聚集体影响折叠的温度敏感的突变体，干扰寿命和压力信号。利用实验室的专业知识和C. elegans，特别是能够遗传调节途径调节生物衰老和应激反应，我们建议解剖的分子机制控制有毒蛋白质和细胞折叠能力之间的相互作用。此外，这些研究应该有助于理解蛋白质错误折叠疾病的多因素性质。

DESCRIPTION (provided by applicant): The proposed research aims at defining the common mechanisms of proteotoxicity exhibited by various disease-related aggregation-prone proteins, and understanding the role of molecular chaperones and stress signaling pathways in modulating folding homeostasis challenged by this proteotoxicity. Specifically, it addresses the hypothesis that expression of aggregation-prone protein affects folding of other cellular proteins, that this effect is mediated by chaperone networks and stress signaling pathways, and that decline in the cellular folding capacity underlies the age-related exacerbation of protein-folding diseases. Preliminary data support this proposition, showing that poly-glutamine aggregates affect folding of the temperature-sensitive mutants, as does interference with longevity and stress signaling. Using the expertise of the lab and the distinct advantages of C. elegans, in particular the ability to genetically modulate the pathways regulating both organismal aging and stress responses, we propose to dissect the molecular mechanisms controlling the interplay between toxic proteins and the cellular folding capacity. In addition, these studies should help in understanding the multifactorial nature of protein-misfolding diseases.