학술논문
PA28[alpha][beta] overexpression enhances learning and memory of female mice without inducing 20S proteasome activity
Document Type
Report
Author
Source
BMC Neuroscience. November 6, 2018, Vol. 19 Issue 1
Subject
Language
English
ISSN
1471-2202
Abstract
Author(s): Julia Adelöf[sup.1,2] , My Andersson[sup.3] , Michelle Porritt[sup.2] , Anne Petersen[sup.1] , Madeleine Zetterberg[sup.1] , John Wiseman[sup.2] and Malin Hernebring[sup.1,2] Background The proteasome is a sophisticated multi-subunit protease comprising [...]
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 PA28[alpha][beta] activates hydrolysis of small nonubiquitinated peptides and possesses protective functions upon oxidative stress and proteinopathy. The effect of PA28[alpha][beta] activity on behavior and memory function is, however, not known. We generated a mouse model that overexpresses PA28[alpha] (PA28[alpha]OE) to understand PA28[alpha][beta] function during healthy adult homeostasis via assessment of physiological and behavioral profiles, focusing on female mice. Results PA28[alpha] and PA28[beta] protein levels were markedly increased in all PA28[alpha]OE tissues analyzed. PA28[alpha]OE 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 PA28[alpha]OE were female specific, but could not be explained by alterations in estrogen serum levels or hippocampal regulation of estrogen receptor [beta]. Further, there were no differences in hippocampal protein expression of neuronal or synaptic markers between PA28[alpha]OE and WT. Biochemical analysis of hippocampal extracts demonstrated that PA28[alpha] overexpression did not increase PA28-20S peptidase activity or decrease K48-polyubiquitin levels. Instead, PA28[alpha]OE exhibited elevated efficiency in preventing aggregation in the hippocampus. Conclusions This study reveals, for the first time, a connection between PA28[alpha][beta] and neuronal function. We found that PA28[alpha] overexpressing female mice displayed reduced depressive-like behavior and enhanced learning and memory. Since the positive effects of PA28[alpha] overexpression arose without an activation of 20S proteasome capacity, they are likely independent of PA28[alpha][beta]'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 PA28[alpha][beta] in the brain. Keywords: PA28[alpha][beta], Learning and memory, F2 hybrid transgenic mice, Behavioral phenotyping, 20S proteasome, Proteasome capacity, K48-linked protein ubiquitination
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 PA28[alpha][beta] activates hydrolysis of small nonubiquitinated peptides and possesses protective functions upon oxidative stress and proteinopathy. The effect of PA28[alpha][beta] activity on behavior and memory function is, however, not known. We generated a mouse model that overexpresses PA28[alpha] (PA28[alpha]OE) to understand PA28[alpha][beta] function during healthy adult homeostasis via assessment of physiological and behavioral profiles, focusing on female mice. Results PA28[alpha] and PA28[beta] protein levels were markedly increased in all PA28[alpha]OE tissues analyzed. PA28[alpha]OE 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 PA28[alpha]OE were female specific, but could not be explained by alterations in estrogen serum levels or hippocampal regulation of estrogen receptor [beta]. Further, there were no differences in hippocampal protein expression of neuronal or synaptic markers between PA28[alpha]OE and WT. Biochemical analysis of hippocampal extracts demonstrated that PA28[alpha] overexpression did not increase PA28-20S peptidase activity or decrease K48-polyubiquitin levels. Instead, PA28[alpha]OE exhibited elevated efficiency in preventing aggregation in the hippocampus. Conclusions This study reveals, for the first time, a connection between PA28[alpha][beta] and neuronal function. We found that PA28[alpha] overexpressing female mice displayed reduced depressive-like behavior and enhanced learning and memory. Since the positive effects of PA28[alpha] overexpression arose without an activation of 20S proteasome capacity, they are likely independent of PA28[alpha][beta]'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 PA28[alpha][beta] in the brain. Keywords: PA28[alpha][beta], Learning and memory, F2 hybrid transgenic mice, Behavioral phenotyping, 20S proteasome, Proteasome capacity, K48-linked protein ubiquitination