2015年7月6日 訊 /生物谷BIOON/ --近日，發表於國際雜誌Neuron和Cell Reports上的兩篇研究論文中，來自哥倫比亞大學醫學中心的研究人員通過研究揭開了大腦維持長效記憶的秘訣，文章中研究者發現，朊病毒樣蛋白質對於維持小鼠及其它哺乳動物大腦的長期記憶非常關鍵，而朊病毒樣蛋白是一種類似於朊病毒的蛋白，朊病毒可以引發庫傑二氏病和狂牛症等。
當長效記憶在大腦中形成後，就會在神經元間建立新的連接來幫助儲存記憶，但這種物理性的連接必須作為一種記憶來進行維持，隨著時間流逝這些記憶都會消散，很多研究者目前都在尋找可以維持長效記憶的分子，但目前並沒有任何頭緒；這項研究中，研究者所發現的記憶性分子是朊病毒蛋白的正常版本，朊病毒是一類特殊的具有感染性的蛋白，並不像其它蛋白，朊病毒會進行自我增殖，同時還會誘導其它蛋白呈現出可替換的形狀。
當朊病毒在細胞中，尤其是在神經元中形成時，其就會通過形成聚集物來引發細胞損傷，朊病毒的聚集物具有較高的穩定性，而且其會在所感染的組織中進行累積，引發組織損傷和細胞死亡。死亡的細胞會釋放朊病毒蛋白，隨後就會被其它細胞所吸收，進而感染朊病毒，朊病毒作為異常的蛋白質會引發狂牛症，同時其還和多種神經變性疾病的發病有關，比如阿爾茲海默氏症等。
相反，具功能性的朊病毒蛋白在細胞中扮演著重要的生理學功能，但其卻並不會引發疾病發生。研究者Kausik Si說道，我們在海螺中鑑別出了功能性的朊病毒，而且發現這些朊病毒可以維持長效的記憶力，而且最近研究者通過在實驗室研究，在小鼠機體中發現了一種名為CPEB3的類似朊病毒的蛋白也具有維持機體長效記憶的功能。
隨後研究者揭示了神經元細胞中CPEB3蛋白如何進行長期記憶的維持，類似於引發疾病的朊病毒，功能性的朊病毒顆粒有兩種類型，可溶解形式和易於聚集的形式；當機體形成長期記憶時，新的突觸連接就會形成，隨後突觸中可溶解的朊病毒就會轉化成為聚集性的朊病毒，這種聚集性的朊病毒會開啟維持大腦長期記憶的蛋白質合成過程。
隨著這種聚集作用的進行，大腦中的長效記憶就會被維持住，朊病毒聚集物會通過持續性地將可溶解的朊病毒轉化為聚集形式的蛋白來進行更新再生；最後研究者表示，在人類機體中或許也存在類似功能的蛋白來維持大腦的長期記憶，當然後期還需要更多研究來證實，長期記憶過程是一項非常複雜的過程，而且在其過程中還涉及許多其它的調節性組分，因此研究者後期還將尋找一些新型的對於長期記憶功能維持非常重要的組分。（生物谷Bioon.com）
本文系生物谷原創編譯整理，歡迎轉載！轉載請註明來源並附原文連結。更多資訊請下載生物谷APP.
The Persistence of Hippocampal-Based Memory Requires Protein Synthesis Mediated by the Prion-like Protein CPEB3
Luana Fioriti, Cory Myers, Yan-You Huang, Xiang Li, Joseph S. Stephan, Pierre Trifilieff, Luca Colnaghi, Stylianos Kosmidis, Bettina Drisaldi, Elias Pavlopoulos, Eric R. Kande
Consolidation of long-term memories depends on de novo protein synthesis. Several translational regulators have been identified, and their contribution to the formation of memory has been assessed in the mouse hippocampus. None of them, however, has been implicated in the persistence of memory. Although persistence is a key feature of long-term memory, how this occurs, despite the rapid turnover of its molecular substrates, is poorly understood. Here we find that both memory storage and its underlying synaptic plasticity are mediated by the increase in level and in the aggregation of the prion-like translational regulator CPEB3 (cytoplasmic polyadenylation element-binding protein). Genetic ablation of CPEB3 impairs the maintenance of both hippocampal long-term potentiation and hippocampus-dependent spatial memory. We propose a model whereby persistence of long-term memory results from the assembly of CPEB3 into aggregates. These aggregates serve as functional prions and regulate local protein synthesis necessary for the maintenance of long-term memory.
SUMOylation Is an Inhibitory Constraint that Regulates the Prion-like Aggregation and Activity of CPEB3
Bettina Drisaldi6, Luca Colnaghi6, Luana Fioriti6, Nishta Rao, Cory Myers, Anna M. Snyder, Daniel J. Metzger, Jenna Tarasoff, Edward Konstantinov, Paul E. Fraser, James L. Manley, Eric R. Kandel
Protein synthesis is crucial for the maintenance of long-term-memory-related synaptic plasticity. The prion-like cytoplasmic polyadenylation element-binding protein 3 (CPEB3) regulates the translation of several mRNAs important for long-term synaptic plasticity in the hippocampus. Here, we provide evidence that the prion-like aggregation and activity of CPEB3 is controlled by SUMOylation. In the basal state, CPEB3 is a repressor and is soluble. Under these circumstances, CPEB3 is SUMOylated in hippocampal neurons both in vitro and in vivo. Following neuronal stimulation, CPEB3 is converted into an active form that promotes the translation of target mRNAs, and this is associated with a decrease of SUMOylation and an increase of aggregation. A chimeric CPEB3 protein fused to SUMO cannot form aggregates and cannot activate the translation of target mRNAs. These findings suggest a model whereby SUMO regulates translation of mRNAs and structural synaptic plasticity by modulating the aggregation of the prion-like protein CPEB3.