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FUGE-Funksjonell genomforskn.i Norg

Protein aggregation and degradation in aging and disease: Role of polyubiquitination and autophagy

Tildelt: kr 8,6 mill.

Hundreds of proteins encoded by the human genome have the propensity to form cytoplasmic aggregates under certain conditions. Although the mechanisms of intracellular protein aggregation are poorly understood, it is well known that deposits of aggregatete d proteins are highly associated with aging and neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's disease. Clarifying how intracellular protein aggregates form, and how they are degraded, is thus predicted to yield novel therape utic targets in these diseases. In this joint project, involving research groups at the University of Tromsø and the Norwegian Radium Hospital, we aim to investigate how normal cells recognize and dispose of cytoplasmic protein aggregates, and how protein aggregates affect cellular functions. Polyubiquitination of protein aggregates is thought to facilitate their degradation, although proteasomes appear to of minor importance for their catabolism. In contrast, autophagy, a process that involves lysosomal degradation of cytoplasm, appears to play an important role in the degradation of protein aggregates. We will pursue recent clues our laboratories have obtained concerning the cellular machineries that recognize and degrade polyubiquitinated protein aggre gates. These analyses will involve proteomics, structural biology, molecular imaging and animal models. Using microarray technology, we will also investigate how protein aggregates affect gene expression in a cellular model. Finally, we will investigate t he activation and localization of the autophagic machinery in clinical samples from diseased brains. This project is thus expected to yield information that will significantly improve our understanding of the interactions between protein aggregates and ce lls and organisms, thus guiding novel therapeutic interventions.


FUGE-Funksjonell genomforskn.i Norg