| Damaged proteins are harmful to cells and when they accumulate they can lead to cell death. Cells control protein damage by refolding or degrading the damaged proteins. When these functions are impaired, for example during chronic environmental stress or aging, damaged proteins will accumulate. Cells can then protect themselves by sequestering these proteins in densely packed fibres for storage in intracellular aggregates. The mechanisms underlying sequestration and inclusion formation and how they relate to cellular aging are still largely unknown, but they can be well studied using the C. elegans worm model. In my pioneering work, I was able to find key genes which alter the number of aggregates. In particular, my recent work has indicated that the moag-4 gene regulates the formation of protein-misfolding intermediates, which are required for aggregate formation, and lifespan. This aggregate promoting activity of moag-4 is unprecedented. The proposed project aims to elucidate the molecular mechanism for moag-4 and the pathway in which it is operating. It will focus on the following tasks: i) Development of techniques to visualize and characterize intermediate protein misfolding and aggregation steps in C. elegans. ii) Investigation of molecular interactions of moag-4 with aggregation intermediates. iii) Identification of genetic interactions of moag-4 with the insulin signalling pathway, a known aging and aggregation modifying pathway. iv) Identification and characterization of other components of the aggregate formation pathway. This fundamental research project in the worm will uncover an unexplored cellular protein quality control mechanism and will deepen our understanding of how cells cope with the constant challenges to protein stability from within and from outside the cell. |
