| 1. |
- Fredriksson, Åsa, 1968, et al.
(författare)
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Effects of aging and reproduction on protein quality control in soma and gametes of Drosophila melanogaster
- 2012
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Ingår i: Aging Cell. - : Wiley. - 1474-9718. ; 11:4, s. 634-643
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Tidskriftsartikel (refereegranskat)abstract
- In organisms with a somagerm demarcation, the germline must be preserved such that harmful damage is not transmitted to the offspring. Keeping the progeny free of damage may be achieved by gametes enjoying elevated, and/or more functional, homeostatic maintenance systems. This possibility was approached here by testing whether the soma and maturating oocytes (eggs) dissected from female Drosophila melanogaster in reproductive ages display differential capacities for protein quality control and whether these capacities change during aging and mating. Eggs exhibited a high capacity to prevent protein aggregation, strong capacity for 26S proteasome-dependent degradation and reduced levels of oxidatively damaged (carbonylated) proteins compared to the soma. The capacity to prevent protein aggregation was not affected in either soma or eggs by age and/or mating, while the 26S proteasome capacity declined in the soma but was maintained in the eggs of aged females. However, the levels of carbonylated proteins increased with age in both soma and eggs, and this increase was more pronounced in females allowed to mate continuously. Furthermore, the levels of carbonylated proteins in the eggs of mated flies correlated negatively with the propensity of the eggs to develop into an adult fly. In young flies, mating caused a decrease in 26S proteasome capacity and an increase in protein carbonylation in the soma, but not in the eggs. These results are in line with trade-off theories of aging where aging is considered a consequence of investment in reproduction over somatic maintenance.
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| 2. |
- Adelöf, Julia, 1990, et al.
(författare)
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Conclusions from a behavioral aging study on male and female F2 hybrid mice on age-related behavior, buoyancy in water-based tests, and an ethical method to assess lifespan.
- 2019
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Ingår i: Aging. - : Impact Journals, LLC. - 1945-4589. ; 11:17, s. 7150-7168
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Tidskriftsartikel (refereegranskat)abstract
- Due to strain-specific behavioral idiosyncrasies, inbred mouse strains are suboptimal research models for behavioral aging studies. The aim of this study is to determine age-related behavioral changes of F2 hybrid C57BL/6NxBALB/c male and female mice. Lifespan was followed (nmales=48, nfemales=51) and cohorts of mature adult (7 months), middle-aged (15 months), and old mice (22 months of age; n=7-12 per group) were assessed regarding open-field activity, exploration, passive avoidance learning/memory, and depressive-like behavior. We found that both males and females demonstrated decreased exploratory behavior with age, while memory and depressive-like behavior were maintained. Females exhibited enhanced depressive-like behavior compared to males; however, a correlation between fat mass and swimming activity in the test directly accounted for 30-46% of this behavioral sex difference. In addition, we suggest a method to qualitatively estimate natural lifespan from survival analyses in which animals with signs of pain or severe disease are euthanized. This is, to our knowledge, the first behavioral study to consider both sex and aging in hybrid mice. We here define decreased exploratory behavior as a conserved hallmark of aging independent of sex, highlight the effect of buoyancy in water tests, and provide a method to assay lifespan with reduced animal suffering.
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| 3. |
- Adelöf, Julia, 1990, et al.
(författare)
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PA28α overexpressing female mice maintain exploratory behavior and capacity to prevent protein aggregation in hippocampus as they age.
- 2021
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Ingår i: Aging cell. - : Wiley. - 1474-9726 .- 1474-9718. ; 4:29
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Tidskriftsartikel (refereegranskat)abstract
- With age, protein damage accumulates and increases the risk of age-related diseases. The proteasome activator PA28αβ is involved in protein damage clearance during early embryogenesis and has demonstrated protective effects against proteinopathy. We have recently discovered that adult female mice overexpressing PA28α (PA28αOE) have enhanced learning and memory, and protein extracts from their hippocampi prevent aggregation more efficiently than wild type. In this study, we investigated the effect of overexpressing PA28α on aging using C57BL/6N×BALB/c F2 hybrid mice. We found that the hippocampal anti-aggregation effect was maintained in young adult (7months) to middle-aged (15months) and old (22months) PA28αOE females. While the PA28αOE influence on learning and memory gradually decreased with aging, old PA28αOE females did not display the typical drop in explorative behavior-a behavioral hallmark of aging-but were as explorative as young mice. PA28αOE lowered PA28-dependent proteasome capacity in both heart and hippocampus, and there was no indication of lower protein damage load in PA28αOE. The life span of PA28αOE was also similar to wild type. In both wild type and PA28αOE, PA28-dependent proteasome capacity increased with aging in the heart, while 26S and 20S proteasome capacities were unchanged in the timepoints analyzed. Thus, PA28αOE females exhibit improved hippocampal ability to prevent aggregation throughout life and enhanced cognitive capabilities with different behavioral outcomes dependent on age; improved memory at early age and a youth-like exploration at old age. The cognitive effects of PA28αβ combined with its anti-aggregation molecular effect highlight the therapeutical potential of PA28αβ in combating proteinopathies.
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| 4. |
- Adelöf, Julia, 1990, et al.
(författare)
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PA28αβ overexpression enhances learning and memory of female mice without inducing 20S proteasome activity
- 2018
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Ingår i: BMC Neuroscience. - : Springer Science and Business Media LLC. - 1471-2202. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The proteasome system plays an important role in synaptic plasticity. Induction and maintenance of long term potentiation is directly dependent on selective targeting of proteins for proteasomal degradation. The 20S proteasome activator PA28αβ activates hydrolysis of small nonubiquitinated peptides and possesses protective functions upon oxidative stress and proteinopathy. The effect of PA28αβ activity on behavior and memory function is, however, not known. We generated a mouse model that overexpresses PA28α (PA28αOE) to understand PA28αβ function during healthy adult homeostasis via assessment of physiological and behavioral profiles, focusing on female mice. RESULTS: PA28α and PA28β protein levels were markedly increased in all PA28αOE tissues analyzed. PA28αOE displayed reduced depressive-like behavior in the forced swim test and improved memory/learning function assessed by intersession habituation in activity box and shuttle box passive avoidance test, with no significant differences in anxiety or general locomotor activity. Nor were there any differences found when compared to WT for body composition or immuno-profile. The cognitive effects of PA28αOE were female specific, but could not be explained by alterations in estrogen serum levels or hippocampal regulation of estrogen receptor β. Further, there were no differences in hippocampal protein expression of neuronal or synaptic markers between PA28αOE and WT. Biochemical analysis of hippocampal extracts demonstrated that PA28α overexpression did not increase PA28-20S peptidase activity or decrease K48-polyubiquitin levels. Instead, PA28αOE exhibited elevated efficiency in preventing aggregation in the hippocampus. CONCLUSIONS: This study reveals, for the first time, a connection between PA28αβ and neuronal function. We found that PA28α overexpressing female mice displayed reduced depressive-like behavior and enhanced learning and memory. Since the positive effects of PA28α overexpression arose without an activation of 20S proteasome capacity, they are likely independent of PA28αβ's role as a 20S proteasome activator and instead depend on a recognized chaperone-like function. These findings suggest that proteostasis in synaptic plasticity is more diverse than previously reported, and demonstrates a novel function of PA28αβ in the brain.
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| 5. |
- Adelöf, Julia, 1990, et al.
(författare)
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Survival-Span Method: How to Qualitatively Estimate Lifespan to Improve the Study of Aging, and not Disease, in Aging Studies
- 2021
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Ingår i: Frontiers in Aging. - : Frontiers Media SA. - 1663-4365 .- 2673-6217. ; 2
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Tidskriftsartikel (refereegranskat)abstract
- Lifespan analyses are important for advancing our understanding of the aging process. There are two major issues in performing lifespan studies: 1) late-stage animal lifespan analysis may include animals with non-terminal, yet advanced illnesses, which can pronounce indirect processes of aging rather than the aging process per se and 2) they often involves challenging welfare considerations. Herein, we present an option to the traditional way of performing lifespan studies by using a novel method that generates high-quality data and allows for the inclusion of excluded animals, even animals removed at early signs of disease. This Survival-span method is designed to be feasibly done with simple means by any researcher and strives to improve the quality of aging studies and increase animal welfare.
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| 6. |
- Hernebring, Malin, 1978, et al.
(författare)
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Elimination of damaged proteins during differentiation of embryonic stem cells
- 2006
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 103:20, s. 7700-7705
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Tidskriftsartikel (refereegranskat)abstract
- During mammalian aging, cellular proteins become increasingly damaged: for example, by carbonylation and formation of advanced glycation end products (AGEs). The means to ensure that offspring are born without such damage are unknown. Unexpectedly, we found that undifferentiated mouse ES cells contain high levels of both carbonyls and AGEs. The damaged proteins, identified as chaperones and proteins of the cytoskeleton, are the main targets for protein oxidation in aged tissues. However, the mouse ES cells rid themselves of such damage upon differentiation in vitro. This elimination of damaged proteins coincides with a considerably elevated activity of the 20S proteasome. Moreover, damaged proteins were primarily observed in the inner cell mass of blastocysts, whereas the cells that had embarked on differentiation into the trophectoderm displayed drastically reduced levels of protein damage. Thus, the elimination of protein damage occurs also during normal embryonic development in vivo. This clear-out of damaged proteins may be a part of a previously unknown rejuvenation process at the protein level that occurs at a distinct stage during early embryonic development
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| 7. |
- Hernebring, Malin, 1978, et al.
(författare)
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H2O2-induced cataract as a model of age-related cataract: Lessons learned from overexpressing the proteasome activator PA28αβ in mouse eye lens.
- 2021
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Ingår i: Experimental eye research. - : Elsevier BV. - 1096-0007 .- 0014-4835. ; 203
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Tidskriftsartikel (refereegranskat)abstract
- Cataract, the world-leading cause of blindness, is formed when crystallin aggregates cloud the eye lens. We overexpressed PA28αβ, a proteasome activator with properties protective against aggregation and oxidative stress, and examined whether they are less prone to develop cataract arisen from aging and/or hydrogen peroxide (H2O2) treatment. Another objective of this work was to compare the H2O2-induced cataracts of mouse lenses ex vivo to cataracts formed upon aging in mice. As part of an aging study of F2 hybrid C57BL/6NxBALB/c mice, ocular lenses of mature adult (7 months), middle-aged (15 months), and old (22 months of age) PA28αOE mice and their wildtype littermates (n=22-44 lenses per group) were dissected and evaluated with regard to their cataractous state. In parallel, ocular lenses from 3 to 4 months old PA28αOE and wildtype C57BL/6N littermates were treated with 100μM H2O2 every 24h for 7 days, with progression of cataract and physical appearance monitored daily. Lenses from both studies were also subjected to analysis of oxidative protein damage (carbonylation) and protein solubility. We found that overexpression of PA28αβ had no effect on neither age-related nor H2O2-induced cataract and conclude that overexpression of PA28αβ does not protect mice from developing cataract. The inefficiency of PA28αβ against cataract could be due to its anti-aggregation activity being already excessively present in the eye lens, exerted by crystallins. Crystallins are likely also constituting the 20-25kDa proteins that were the dominant carbonyl targets in the eye lens irrespective of cataractous state. Assessment of H2O2-induced cataract in relation to age-related cataract demonstrated that high molecular weight protein carbonylation correlates to cataract both in vivo and ex vivo, while reduced protein solubility is more pronounced in age-related cataract. Furthermore, this work highlights vast dissimilarities in the physical manifestations of cataract upon aging and H2O2 ex vivo treatment. Age-related cataract initiation can take various forms, as a vague general blurriness or as a barely visible demarcated opacity, while H2O2-induced cataractogenesis seems to follow a specific scheme. In mice, this scheme begins with relatively opaque peripheral areas emerging that clear up later on as the lenses start to display a hat-like appearance. This transformation takes place synchronous to swelling of the eye lens, and is likely a result of osmotic disturbances causing a phase separation between the viscous lens cortex and the more solid fibers of the lens nucleus.
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| 8. |
- Hernebring, Malin, 1978
(författare)
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Protein Damage Control during Embryonic Stem Cell Differentiation: Role of the Proteasome
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- During the lifespan of organisms ranging from yeast to humans, there is an accumulation of macromolecular damage. However, these organisms produce youthful progeny with low damage levels. This thesis focuses on how this is accomplished. I have analyzed whether the levels of oxidatively damaged proteins change in mouse embryonic stem (ES) cells during the initial steps of cell specification (differentiation) from the pluripotent state. The results show that ES cells contain high levels of proteins modified by carbonyls and advanced glycation end products and that the identity of these damaged proteins, including chaperones and proteins of the cytoskeleton, are the same as those of aged tissues. However, early differentiation is accompanied by a dramatic drop in the damage of such proteins, both in cultured ES cells and in the blastocyst in vivo. //Text removed from public version// Moreover, the results support a model in which the restoration of low levels of protein damage at the start of each generation is achieved, in part, by a maintained capacity of the germ line to rid itself from such damage. //Text removed from public version//
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| 9. |
- Hernebring, Malin, 1978, et al.
(författare)
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Removal of damaged proteins during ES cell fate specification requires the proteasome activator PA28
- 2013
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322 .- 2045-2322. ; 3:3, s. artikel nr 1381-
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Tidskriftsartikel (refereegranskat)abstract
- In embryonic stem cells, removal of oxidatively damaged proteins is triggered upon the first signs of cell fate specification but the underlying mechanism is not known. Here, we report that this phase of differentiation encompasses an unexpected induction of genes encoding the proteasome activator PA28 alpha beta (11S), subunits of the immunoproteasome (20Si), and the 20Si regulator TNF alpha. This induction is accompanied by assembly of mature PA28-20S(i) proteasomes and elevated proteasome activity. Inhibiting accumulation of PA28 alpha using miRNA counteracted the removal of damaged proteins demonstrating that PA28 alpha beta has a hitherto unidentified role required for resetting the levels of protein damage at the transition from self-renewal to cell differentiation.
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| 10. |
- Palmgren, Madelene, et al.
(författare)
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Quantification of the Intracellular Life Time of Water Molecules to Measure Transport Rates of Human Aquaglyceroporins
- 2017
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Ingår i: Journal of Membrane Biology. - : Springer Science and Business Media LLC. - 0022-2631 .- 1432-1424. ; 250:6, s. 629-639
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Tidskriftsartikel (refereegranskat)abstract
- Orthodox aquaporins are transmembrane channel proteins that facilitate rapid diffusion of water, while aquaglyceroporins facilitate the diffusion of small uncharged molecules such as glycerol and arsenic trioxide. Aquaglyceroporins play important roles in human physiology, in particular for glycerol metabolism and arsenic detoxification. We have developed a unique system applying the strain of the yeast Pichia pastoris, where the endogenous aquaporins/aquaglyceroporins have been removed and human aquaglyceroporins AQP3, AQP7, and AQP9 are recombinantly expressed enabling comparative permeability measurements between the expressed proteins. Using a newly established Nuclear Magnetic Resonance approach based on measurement of the intracellular life time of water, we propose that human aquaglyceroporins are poor facilitators of water and that the water transport efficiency is similar to that of passive diffusion across native cell membranes. This is distinctly different from glycerol and arsenic trioxide, where high glycerol transport efficiency was recorded.
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