Misfolded proteins alter the folding capacity of cells

描述（由申请人提供）：本研究旨在确定各种疾病相关的易聚集蛋白所表现出的蛋白质毒性的共同机制，并了解分子伴侣和应激信号通路在调节这种蛋白质毒性所挑战的折叠稳态中的作用。具体来说，它提出了一个假设，即易聚集蛋白的表达会影响其他细胞蛋白的折叠，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蛋白质折叠疾病与年龄相关的恶化的基础。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，就像干扰寿命和应激信号一样。利用实验室的专业知识和秀丽隐杆线虫的独特优势，特别是遗传调节生物体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和细胞折叠能力之间相互作用的分子机制。此外，这些研究应该有助于了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.