Misfolded proteins alter the folding capacity of cells

Northwestern University, Evanston IL

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Abstract

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.