Lack of DREAM Protein Enhances Learning and Memory and Slows Brain Aging
Lack of DREAM Protein Enhances Learning and Memory and Slows Brain Aging
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DOI：
10.1016/j.cub.2008.11.056
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发表时间：
2009-01-13
期刊：
影响因子：
9.2
通讯作者：
Manuel Carrion, Angel
中科院分区：
文献类型：
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作者：
Fontan-Lozano, Angela;Romero-Granados, Rocio;Manuel Carrion, Angel
衰老过程中的记忆缺陷影响着数百万人，并且常常令相关人员感到不安。剖析学习和记忆的分子控制对于理解并可能增强认知功能至关重要。最近也发现老年记忆丧失与 Ca2+ 稳态改变有关。我们之前已经鉴定出 DREAM（下游调节元件拮抗调节剂），它是 EF-hand 蛋白神经元 Ca2+ 传感器超家族的成员，在不同的细胞区室中具有特定的作用 [1, 2]。在细胞核中，DREAM 是一种 Ca2+ 依赖性转录抑制因子，与特定 DNA 特征结合 [1, 3]，或与调节其转录特性的核蛋白相互作用 [4-6]。此外，我们和其他人还发现，梦想突变体 (dream(-/-)) 小鼠表现出明显的镇痛作用 [7, 8]。在这里，我们报告说，梦想（-/-）小鼠表现出与认知改善相关的显着增强的学习和突触可塑性。从机制上讲，DREAM 以 Ca2+ 依赖性方式发挥关键记忆因子 CREB 的负调节作用，而 DREAM 的缺失会促进学习过程中 CREB 依赖性转录。有趣的是，18 个月大的 Dream(-/-) 小鼠表现出与年轻小鼠相似的学习和记忆能力。此外，梦想的丧失可以防止大脑因衰老而退化。这些数据将 Ca2+ 调节的“疼痛基因”DREAM 确定为记忆和大脑衰老的新型关键调节因子。
Memory deficits in aging affect millions of people and are often disturbing to those concerned. Dissection of the molecular control of learning and memory is paramount to understand and possibly enhance cognitive functions. Oldage memory loss also has been recently linked to altered Ca2+ homeostasis. We have previously identified DREAM (downstream regulatory element antagonistic modulator), a member of the neuronal Ca2+ sensor superfamily of EF-hand proteins, with specific roles in different cell compartments [1, 2]. In the nucleus, DREAM is a Ca2+-dependent transcriptional repressor, binding to specific DNA signatures [1, 3], or interacting with nucleoproteins regulating their transcriptional properties [4-6]. Also, we and others have shown that dream mutant (dream(-/-)) mice exhibit marked analgesia [7, 8]. Here we report that dream(-/-) mice exhibit markedly enhanced learning and synaptic plasticity related to improved cognition. Mechanistically, DREAM functions as a negative regulator of the key memory factor CREB in a Ca2+-dependent manner, and loss of DREAM facilitates CREB-dependent transcription during learning. Intriguingly, 18-month-old dream(-/-) mice display learning and memory capacities similar to young mice. Moreover, loss of DREAM protects from brain degeneration in aging. These data identify the Ca2+-regulated "pain gene" DREAM as a novel key regulator of memory and brain aging.