Functional Analysis of the Proteasome in
Eukaryotic Organisms
av
Marianthi Sakellari
Akademisk avhandling
Avhandling för medicine doktorsexamen i Medicinsk vetenskap med inriktning mot biomedicin,
som kommer att försvaras offentligt torsdagen den 23 april 2020, Örebro universitet
Opponent: Professor Richard G.A. Faragher University of Brighton, Brighton, UK
Örebro universitet
Institutionen för medicinska vetenskaper 701 82 ÖREBRO
Abstract
Marianthi Sakellari (2020): Functional Analysis of the Proteasome in Eukaryotic Organisms. Örebro Studies in Medicine 208.
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 char-acterized by reduced proteasome function that leads to proteotoxic stress. Compound-related interventions, that ameliorate proteasome system col-lapse, retard aging process. In the present thesis, 18α-glycyrrhetinic acid (18α-GA), a natural compound with known proteasome activating prop-erties in cells, was indicated to activate proteasome also in the multicellu-lar organism Caenorhabditis elegans (C. elegans). Evaluation of the anti-aging and protein anti-aggregation effects of this bioactive compound indicated that 18α-GA promoted longevity in nematodes through pro-teasome- and SKN-1-mediated activation and decelerated Alzheimer’s disease progression and neuropathology both in nematodes and neuronal cells. Additionally, the crosstalk between protein synthesis and pro-teasome-mediated protein degradation was analyzed in eukaryotic organ-isms under various cellular conditions. Protein synthesis inhibition was observed to increase proteasome function and assembly in human prima-ry embprima-ryonic fibroblasts, with heat shock protein chaperone machineprima-ry 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. Fur-thermore, proteasome activation by means which have also pro-longevity effects decreased the protein synthesis rate both in human fibroblast cells and nematodes. This thesis suggests: 1) that a diet-derived compound could act as a pro-longevity and anti-aggregation agent in the context of a multicellular organism and 2) the existence of a complex interplay be-tween anabolic and catabolic processes under different cellular condi-tions, across species.
Keywords: Proteasome; Proteasome activation; Protein synthesis inhibition; Hsp70; Hsp90; Proteostasis; Aging; Alzheimer’s disease; Caenorhabditis elegans; Lifespan extension; SKN-1
Marianthi Sakellari, (1) School of Medical Sciences, Örebro University, SE-701 82 Örebro, Sweden, (2) Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 48 Vassileos Constantinou Avenue, 11635, Athens, Greece, mirella_sak@hotmail.com
