Effect of cytosolic aggregation on protein targeting - implications for chaperone competition

• Applicant: Dr. Janine Kirstein-Miles
• Subject Area: Cell Biology
• Term: Funded in 2008
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 70756314

Protein aggregation is a common feature of neurodegenerative diseases such as Huntington, Parkin-son and Alzheimer´s disease. I will use C. elegans, which is an established model for human degene-rative diseases to study cellular and tissue specific responses to protein aggregation. The aim of the research described in this proposal is to elucidate whether expression of polyQ in the cytosol results in a competition for molecular chaperones and thereby affecting the functionality of proteins targeted to the organelles. Using fluorescent imaging techniques, the specific translocation of model proteins into the ER and other organelles will be monitored upon induced polyQ aggregation in the cytosol. I propose to determine the threshold of polyQ for interference with the trafficking process and the functionality of the protein and its dependence on longevity and the capacity of the PQC system. For that, the protein trafficking process will be analyzed in various mutant backgrounds resulting in a shortened or expanded lifespan and a deletion or overexpression of a particular chaperone or chaperone network, respectively. As a next step, I aim (i) to compare the simultaneous intracellular trafficking to different organelles using a dual labeling approach and (ii) to study the impact of aggregation on protein trafficking in different tissues such as neuronal and muscle cells. Finally, based on the obtained data, a genetic approach using RNAi is planned to identify novel modifiers of the interrelation between protein aggregation and intracellular signaling/ trafficking.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Richard I. Morimoto