Misfolded proteins alter the folding capacity of cells

描述(申请人提供)：这项拟议的研究旨在确定各种疾病相关聚集倾向蛋白表现出的蛋白毒性的共同机制，并了解分子伴侣和胁迫信号通路在调节折叠动态平衡中的作用。具体地说，它解决了这样的假设，即易于聚集的蛋白质的表达影响其他细胞蛋白质的折叠，这种影响是由伴侣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。初步数据支持这一观点，表明聚谷氨酰胺聚集体影响温度敏感突变体的折叠，以及对寿命和压力信号的干扰。利用实验室的专业知识和线虫的独特优势，特别是在基因上调节调节生物衰老和应激反应的途径的能力，我们建议剖析控制有毒蛋白质之间的相互作用和细胞折叠能力的分子机制。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.