Functional analysis of the proteasome in eukaryotic organisms

Abstract: Proteasome degradation machinery is responsible for the turnover of a huge variety of normal and abnormal proteins, thus regulating a plethora of cellular processes. Aging is an inevitable biological process that is characterized by reduced proteasome function that leads to proteotoxic stress. Compound-related interventions, that ameliorate proteasome system collapse, retard aging process. In the present thesis, 18α-glycyrrhetinic acid (18α-GA), a natural compound with known proteasome activating properties in cells, was indicated to activate proteasome also in the multicellular organism Caenorhabditis elegans (C. elegans). Evaluation of the antiaging and protein anti-aggregation effects of this bioactive compound indicated that 18α-GA promoted longevity in nematodes through proteasome-and SKN-1-mediated activation and decelerated Alzheimer’sdisease progression and neuropathology both in nematodes and neuronal cells. Additionally, the crosstalk between protein synthesis and proteasome-mediated protein degradation was analyzed in eukaryotic organisms under various cellular conditions. Protein synthesis inhibition was observed to increase proteasome function and assembly in human primary embryonic fibroblasts, with heat shock protein chaperone machinery to contribute to the elevated proteasome assembly. Alternatively, protein synthesis inhibition increased the protein levels of specific proteasome subunits without influencing the proteasome activity in C. elegans. Furthermore, proteasome activation by means which have also pro-longevity effects decreased the protein synthesis rate both in human fibroblast cellsand nematodes. This thesis suggests: 1) that a diet-derived compound could act as a pro-longevity and anti-aggregation agent in the context of amulticellular organism and 2) the existence of a complex interplay between anabolic and catabolic processes under different cellular conditions, across species.