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18α-Glycyrrhetinic Acid Proteasome Activator Decelerates Aging and Alzheimer's Disease Progression in Caenorhabditis elegans and Neuronal Cultures
Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece; Faculty of Biology and Pharmacy, Institute of Nutrition, Friedrich Schiller University of Jena, Jena, Germany.
Örebro University, School of Medical Sciences. Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece.
Translational Cancer Biology Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.
Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion, Greece; Faculty of Medicine, Department of Basic Sciences, University of Crete, Heraklion, Greece.
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2016 (English)In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 25, no 16, p. 855-869Article in journal (Refereed) Published
Abstract [en]

Aims: Proteasomes are constituents of the cellular proteolytic networks that maintain protein homeostasis through regulated proteolysis of normal and abnormal (in any way) proteins. Genetically mediated proteasome activation in multicellular organisms has been shown to promote longevity and to exert protein antiaggregation activity. In this study, we investigate whether compound-mediated proteasome activation is feasible in a multicellular organism and we dissect the effects of such approach in aging and Alzheimer's disease (AD) progression.

Results: Feeding of wild-type Caenorhabditis elegans with 18α-glycyrrhetinic acid (18α-GA; a previously shown proteasome activator in cell culture) results in enhanced levels of proteasome activities that lead to a skinhead-1- and proteasome activation-dependent life span extension. The elevated proteasome function confers lower paralysis rates in various AD nematode models accompanied by decreased Aβ deposits, thus ultimately decelerating the progression of AD phenotype. More importantly, similar positive results are also delivered when human and murine cells of nervous origin are subjected to 18α-GA treatment.

Innovation: This is the first report of the use of 18α-GA, a diet-derived compound as prolongevity and antiaggregation factor in the context of a multicellular organism.

Conclusion: Our results suggest that proteasome activation with downstream positive outcomes on aging and AD, an aggregation-related disease, is feasible in a nongenetic manipulation manner in a multicellular organism. Moreover, they unveil the need for identification of antiaging and antiamyloidogenic compounds among the nutrients found in our normal diet.

Place, publisher, year, edition, pages
New Rochelle, USA: Mary Ann Liebert, 2016. Vol. 25, no 16, p. 855-869
Keywords [en]
Proteasome activation, lifespan extension, aging, Alzheimer’s disease, aggregation, proteostasis
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:oru:diva-49639DOI: 10.1089/ars.2015.6494ISI: 000388262600001PubMedID: 26886723OAI: oai:DiVA.org:oru-49639DiVA, id: diva2:921535
Note

Funding Agencies:

U.S. National Institutes of Health National Center for Research Resources

Thales GenAge QALHS AP:10479/3.7.12 MIS380228

MAESTRO by the European Union (European Social Fund)

Operational Program, Education and Lifelong Learning, of the National Strategic Reference Framework (NSRF)

European Union 266486

IKYDA fellowship

Empirikion Foundation Scientific Project

John S. Latsis Public Benefit Foundation

Academy of Finland 259797

COST Actions PROTEOS-TASIS BM1307

GENiE BM1408

COST (European Cooperation in Science and Technology)

Available from: 2016-04-20 Created: 2016-04-05 Last updated: 2020-03-30Bibliographically approved
In thesis
1. Functional analysis of the proteasome in eukaryotic organisms
Open this publication in new window or tab >>Functional analysis of the proteasome in eukaryotic organisms
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Örebro: Örebro University, 2020. p. 116
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 208
Keywords
Proteasome, Proteasome activation, Protein synthesis inhibition, Hsp70, Hsp90, Proteostasis, Aging, Alzheimer’s disease, Caenorhabditis elegans, Lifespan extension, SKN-1
National Category
Other Basic Medicine
Identifiers
urn:nbn:se:oru:diva-79875 (URN)978-91-7529-330-1 (ISBN)
Public defence
2020-04-23, Örebro universitet, Campus USÖ, hörsal C3, Södra Grev Rosengatan 32, Örebro, 13:00 (English)
Opponent
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Available from: 2020-02-14 Created: 2020-02-14 Last updated: 2020-04-07Bibliographically approved

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