Curley, M., Rai, M., Chuang, C.L., Pagala, V., Stephan, A., Coleman, Z., Robles-Murguia, M., Wang, Y.D., Peng, J., Demontis, F. (2024). Transgenic sensors reveal compartment-specific effects of aggregation-prone proteins on subcellular proteostasis during aging.  Cell Rep Methods 4(10): 100875.

FBrf0260707

Research paper

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.

PMC11573793 (PMC) (EuropePMC)