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Functional analysis of the proteasome in eukaryotic organisms
Örebro University, School of Medical Sciences.
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 [en]
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: urn:nbn:se:oru:diva-79875ISBN: 978-91-7529-330-1 (print)OAI: oai:DiVA.org:oru-79875DiVA, id: diva2:1392955
Public defence
2020-04-23, Örebro universitet, Campus USÖ, hörsal C3, Södra Grev Rosengatan 32, Örebro, 13:00 (English)
Opponent
Supervisors
Available from: 2020-02-14 Created: 2020-02-14 Last updated: 2020-03-31Bibliographically approved
List of papers
1. 18α-Glycyrrhetinic Acid Proteasome Activator Decelerates Aging and Alzheimer's Disease Progression in Caenorhabditis elegans and Neuronal Cultures
Open this publication in new window or tab >>18α-Glycyrrhetinic Acid Proteasome Activator Decelerates Aging and Alzheimer's Disease Progression in Caenorhabditis elegans and Neuronal Cultures
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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
Keywords
Proteasome activation, lifespan extension, aging, Alzheimer’s disease, aggregation, proteostasis
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:oru:diva-49639 (URN)10.1089/ars.2015.6494 (DOI)000388262600001 ()26886723 (PubMedID)
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
2. Protein synthesis inhibition induces proteasome assembly and function
Open this publication in new window or tab >>Protein synthesis inhibition induces proteasome assembly and function
2019 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 514, no 1, p. 224-230Article in journal (Refereed) Published
Abstract [en]

Protein synthesis and degradation balance have a crucial role in maintenance of cellular homeostasis and function. The ubiquitin-proteasome system is one of the major cellular proteolytic machineries responsible for the removal of normal, abnormal, denatured or in general damaged proteins. Proteasome is a multisubunit enzyme that consists of the 20S core and the 19S regulatory complexes giving rise to multiple active forms. In the present study we investigated the crosstalk between protein synthesis and proteasome-mediated protein degradation. Pharmacological protein synthesis inhibition led to increased proteasome function and assembly of 30S/26S proteasome complexes, in human primary embryonic fibroblasts. The enhancement in proteasome function counted for the degradation of ubiquitinated, misfolded and oxidized proteins. Additionally, it was found that heat shock proteins 70 and 90 are probably involved in the elevated proteasome assembly. Our results provide an insight on how the mechanisms of protein synthesis, protein degradation and heat shock protein chaperones machinery interact under various cellular conditions.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
Proteasome, Proteasome activation, Protein synthesis inhibition, Hsp70, Hsp90
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:oru:diva-79901 (URN)10.1016/j.bbrc.2019.04.114 (DOI)000469406800033 ()31029420 (PubMedID)2-s2.0-85064700180 (Scopus ID)
Note

Funding Agencies:

Research Funding Program: Thales "GenAge" - European Union  QALHS AP:10479/3.7.12 MIS380228

Greek national funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF) 

Available from: 2020-02-14 Created: 2020-02-14 Last updated: 2020-03-30Bibliographically approved
3. Study of the effects of protein synthesis inhibition on proteasome-mediated protein degradation in Caenorhabditis elegans
Open this publication in new window or tab >>Study of the effects of protein synthesis inhibition on proteasome-mediated protein degradation in Caenorhabditis elegans
(English)Manuscript (preprint) (Other academic)
National Category
Other Basic Medicine
Identifiers
urn:nbn:se:oru:diva-80902 (URN)
Available from: 2020-03-30 Created: 2020-03-30 Last updated: 2020-03-30Bibliographically approved
4. Study of the effects of increased proteasome-mediated proteolysis on protein synthesis rate
Open this publication in new window or tab >>Study of the effects of increased proteasome-mediated proteolysis on protein synthesis rate
(English)Manuscript (preprint) (Other academic)
National Category
Other Basic Medicine
Identifiers
urn:nbn:se:oru:diva-80903 (URN)
Available from: 2020-03-30 Created: 2020-03-30 Last updated: 2020-03-30Bibliographically approved

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Sakellari, Marianthi

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12345673 of 16
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