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

Loss of proteostasis 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.