The anaphase promoting complex is required for memory function in mice
The anaphase promoting complex is required for memory function in mice
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DOI：
10.1101/lm.1998411
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发表时间：
2011-01-01
影响因子：
2
通讯作者：
Fischer, Andre
中科院分区：
文献类型：
--
作者：
Kuczera, Tanja;Stilling, Roman Manuel;Fischer, Andre
学习和记忆过程关键涉及从头蛋白质合成的协调调节。另一方面，已经清楚的是，受调节的蛋白质降解在神经元可塑性和学习行为中也起着重要作用。介导蛋白质降解的关键途径之一是蛋白体蛋白质破坏。后期促进复合物/环体（APC/C）是一种E3泛素连接酶，其靶向蛋白质以通过26 S蛋白酶体降解蛋白质。虽然APC/C对细胞周期进程至关重要，但它也在有丝分裂后神经元中表达，其中它与轴突生长和神经元存活有关。在这项研究中，我们提出了APC/C在学习和记忆功能中的作用，通过产生小鼠，缺乏必要的亚基APC 2从成年前脑兴奋性神经元。这些动物是可以存活的，但在消除恐惧记忆的能力上表现出严重的障碍，这是治疗焦虑症（如恐惧症或创伤后应激障碍）的关键过程。由于失调的蛋白质降解和APC/C活性与神经变性有关，我们还分析了Apc 2缺失在阿尔茨海默病小鼠模型中的作用。在我们的实验设置中，APC 2形式的主要前脑神经元的损失不影响阿尔茨海默病小鼠模型的病理过程。总之，我们的数据提供了遗传学证据，成人前脑中的APC/C活性是认知功能所必需的。
Learning and memory processes critically involve the orchestrated regulation of de novo protein synthesis. On the other hand it has become clear that regulated protein degradation also plays a major role in neuronal plasticity and learning behavior. One of the key pathways mediating protein degradation is proteosomal protein destruction. The anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase that targets proteins for proteosomal degradation by the 26S proteasome. While the APC/C is essential for cell cycle progression it is also expressed in postmitotic neurons where it has been implicated with axonal outgrowth and neuronal survival. In this study we addressed the role of APC/C in learning and memory function by generating mice that lack the essential subunit APC2 from excitatory neurons of the adult forebrain. Those animals are viable but exhibit a severe impairment in the ability to extinct fear memories, a process critical for the treatment of anxiety diseases such as phobia or post-traumatic stress disorder. Since deregulated protein degradation and APC/C activity has been implicated with neurodegeneration we also analyzed the effect of Apc2 deletion in a mouse model for Alzheimer's disease. In our experimental setting loss of APC2 form principle forebrain neurons did not affect the course of pathology in an Alzheimer's disease mouse model. In conclusion, our data provides genetic evidence that APC/C activity in the adult forebrain is required for cognitive function.