Mechanisms Underlying Muscle Development and Maintenance in Drosophila

PROJECT SUMMARY The inability to remove protein aggregates in non-dividing cells such as neurons or muscles is a key factor in the development and progression of neurodegenerative diseases and myopathies and is a cellular hallmark of aging cells. While protein aggregate diseases share common features, the molecular pathways that lead to abnormal protein accumulation cannot be explained by a single mechanism. In protein aggregation diseases that affect skeletal and cardiac muscles, a general trend has emerged in which aggregated proteins and organelles accumulate in regions devoid of sarcomeric proteins. However, the cellular and mechanical triggers that initiate Z-disk disintegration and myofiber displacement are unclear. Here we employ mutations in conserved Drosophila genes as an entry point to uncover cellular and molecular mechanisms that lead to protein aggregation and ultimately cellular degeneration using muscle as a model cell type. Overall, we expect to uncover new proteins that contribute to proteostasis; identify muscle targets of kinase activity; and define how mechanical tension and autophagy cooperate in the clearance of protein aggregates. A powerful combination of genetic analysis, biochemistry, cell biology, and optogenetic approaches will address these questions. We expect that this project will fundamentally advance our understanding of how protein degradation is regulated to prevent cellular degeneration and provide fresh insights into how protein aggregates can be effectively cleared to reduce disease states.