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PA28αβ overexpressi...
PA28αβ overexpression enhances learning and memory of female mice without inducing 20S proteasome activity
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- Adelöf, Julia, 1990 (author)
- Gothenburg University,Göteborgs universitet,University of Gothenburg,AstraZeneca, Sweden,Institutionen för neurovetenskap och fysiologi,Institute of Neuroscience and Physiology
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- Andersson, My (author)
- Lund University,Lunds universitet,Epilepsicentrum,Sektion IV,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Cellulär Neurofysiologi och Epilepsi,Forskargrupper vid Lunds universitet,Epilepsy Center,Section IV,Department of Clinical Sciences, Lund,Faculty of Medicine,Cellular Neurophysiology and Epilepsy group,Lund University Research Groups
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- Porritt, Michelle (author)
- AstraZeneca, Sweden
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- Petersen, Anne, 1962 (author)
- Gothenburg University,Göteborgs universitet,University of Gothenburg,Institutionen för neurovetenskap och fysiologi,Institute of Neuroscience and Physiology
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- Zetterberg, Madeleine, 1969 (author)
- Gothenburg University,Göteborgs universitet,University of Gothenburg,Institutionen för neurovetenskap och fysiologi,Institute of Neuroscience and Physiology
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- Wiseman, John (author)
- AstraZeneca, Sweden
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- Hernebring, Malin, 1978 (author)
- Gothenburg University,Göteborgs universitet,University of Gothenburg,AstraZeneca, Sweden,Institutionen för neurovetenskap och fysiologi,Institute of Neuroscience and Physiology
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(creator_code:org_t)
- 2018-11-06
- 2018
- English.
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In: BMC Neuroscience. - : Springer Science and Business Media LLC. - 1471-2202. ; 19:1
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Keyword
- 20S proteasome
- Behavioral phenotyping
- F2 hybrid transgenic mice
- K48-linked protein ubiquitination
- Learning and memory
- PA28αβ
- Proteasome capacity
- 20S proteasome; Behavioral phenotyping; F2 hybrid transgenic mice; K48-linked protein ubiquitination; Learning and memory; PA28αβ; Proteasome capacity
Publication and Content Type
- art (subject category)
- ref (subject category)
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