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首页> 外文期刊>BMC Neuroscience >PA28αβ overexpression enhances learning and memory of female mice without inducing 20S proteasome activity
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PA28αβ overexpression enhances learning and memory of female mice without inducing 20S proteasome activity

机译：PA28αβ的过表达增强雌性小鼠的学习和记忆能力，而不会诱导20S蛋白酶体活性

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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. 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. 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.
机译：蛋白酶体系统在突触可塑性中起重要作用。长期增强的诱导和维持直接取决于蛋白质对蛋白酶体降解的选择性靶向。 20S蛋白酶体激活剂PA28αβ激活小的未泛素化肽的水解，并在氧化应激和蛋白病时具有保护功能。但是，PA28αβ活性对行为和记忆功能的影响尚不清楚。我们生成了一个过表达PA28α（PA28αOE）的小鼠模型，以通过评估生理和行为特征来了解健康成年体内稳态期间的PA28αβ功能，重点是雌性小鼠。在所分析的所有PA28αOE组织中，PA28α和PA28β蛋白水平均显着升高。 PA28αOE在强迫游泳试验中表现出减少的抑郁样行为，在活动箱和穿梭箱被动回避试验中通过休会习惯化评估其记忆/学习功能得到了改善，而焦虑或一般运动能力没有显着差异。与WT相比，在身体组成或免疫特性上也没有发现任何差异。 PA28αOE的认知作用是女性特异性的，但不能通过雌激素血清水平的改变或雌激素受体β的海马调节来解释。此外，PA28αOE和WT之间的神经元或突触标志物海马蛋白表达没有差异。海马提取物的生化分析表明，PA28α过表达不会增加PA28-20S肽酶活性或降低K48-多聚泛素水平。相反，PA28αOE在预防海马中聚集方面表现出提高的效率。这项研究首次揭示了PA28αβ与神经元功能之间的联系。我们发现，PA28α过表达的雌性小鼠表现出减少的抑郁样行为，并增强了学习和记忆能力。由于PA28α过表达的积极作用是在不激活20S蛋白酶体能力的情况下产生的，因此它们很可能与PA28αβ作为20S蛋白酶体激活剂的作用无关，而是取决于公认的伴侣蛋白样功能。这些发现表明，蛋白突触在突触可塑性中比以前报道的更加多样化，并证明了PA28αβ在大脑中具有新的功能。

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