Transgenic sensors reveal compartment-specific effects of aggregation-prone proteins on subcellular proteostasis during aging

Loss of proteostasis(definition) is a hallmark of aging that underlies many age-related diseases. Different cell compartments experience distinctive challenges in maintaining protein quality control, but how aging regulates subcellular proteostasis remains underexplored. Here, by targeting the misfolding-prone Fluc DM luciferase to the cytoplasm, mitochondria, and nucleus, we established transgenic sensors to examine subcellular proteostasis in Drosophila . Analysis of detergent-insoluble and -soluble levels of compartment-targeted Fluc DM variants indicates that thermal stress, cold shock, and pro-longevity inter-organ signaling differentially affect subcellular proteostasis during aging. Moreover, aggregation-prone proteins that cause different neurodegenerative diseases induce a diverse range of outcomes on Fluc DM insolubility, suggesting that subcellular proteostasis is impaired in a disease-specific manner. Further analyses with Fluc DM and mass spectrometry indicate that pathogenic tau V337M produces an unexpectedly complex regulation of solubility for different Fluc DM variants and protein subsets. Altogether, compartment-targeted Fluc DM sensors pinpoint a diverse modulation of subcellular proteostasis by aging regulators.