臺灣博碩士論文加值系統

長期記憶需要神經活性引導突觸上的蛋白體重組，以調節突觸效能，從而鞏固已形成的記憶。而神經活性藉由調控核醣核酸轉譯可改變受刺激突觸的蛋白質組成。CPEB3 是一個具有序列特異性的核醣核酸結合蛋白，在神經元中抑制其標靶訊息核醣核酸的轉譯，然而NMDA 受體的激活減輕CPEB3 的轉譯抑制。雖然近期的研究揭示了CPEB3 抑制轉譯機制，但對於NMDA 受體訊息如何調控CPEB3 的轉譯活動仍然不清楚。本篇研究表明，神經元在NMDA 的刺激下促使轉譯抑制蛋白CPEB3 降解，並同時伴隨著EGFR 蛋白表現量升高，且大部分蛋白的表現是轉譯過程導致。藉由使用藥物(酵素抑制物)及干擾性核醣核酸的方法，我們發現透過NMDA 受體激活，鈣離子的大量湧入，calpain 2 活化並去除CPEB3 氨基端，保留具有核醣核酸結合區域的羧基端。經calpain 2 裂解的CPEB3 片段可與RNA結合，但不具轉譯抑制功效。因此NMDA 激活calpain 2 而導致的CPEB3 裂解，可解釋神經活性相關的CPEB3 標靶訊息核醣核酸的轉譯。

Long-term memory requires the activity-dependent reorganization of the synaptic proteome to modulate synaptic efficacy and consequently consolidate memory. Activity-regulated RNA translation can change the protein composition at the stimulated synapse. Cytoplasmic polyadenylation element-binding protein 3 (CPEB3) is a sequence-specific RNA-binding protein that represses translation of its target mRNAs in neurons, while activation of N-methyl-D-aspartic acid (NMDA) receptors alleviates this repression. Although recent research has revealed the mechanism of CPEB3-inhibited translation, how NMDA receptor signaling modulates the translational activity of CPEB3 remains unclear. This study shows that the repressor CPEB3 is degraded in NMDA-stimulated neurons and that the degradation of CPEB3 is accompanied by the elevated expression of CPEB3's target, epidermal growth factor receptor (EGFR), mostly at the translational level. Using pharmacological and knockdown approaches, we have identified that calpain 2, activated by the influx of calcium through NMDA receptors, proteolyzes the N-terminal repression motif but not the C-terminal RNA-binding domain of CPEB3. As a result, the calpain 2-cleaved CPEB3 fragment binds to RNA but fails to repress translation. Therefore, the cleavage of CPEB3 by NMDA-activated calpain 2 accounts for the activity-related translation of CPEB3-targeted RNAs.

CONTENT…………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………I
FIGURE CONTENT………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………III
中文摘要……………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………V
ABSTRACT…………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………VI
INTRODUCTION………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………1
1. Neuronal activity-driven reorganization of synaptic proteome……………………………………………………………………………………………………………………1
1.1 Activity-dependent alteration of synaptic proteome through translational control…………………………………………………………2
1.2 Activity-dependent alteration of synaptic proteome through proteolytic control………………………………………………………………4
2. The calpain family of proteases…………………………………………………………………………………………………………………………………………………………………………………………………5
2.1 Domain structure……………………………………………………………………………………………………………………………………………………………………………………………………………………………………5
2.2 Physiological roles……………………………………………………………………………………………………………………………………………………………………………………………………………………………6
2.3 Calpain function in the brain…………………………………………………………………………………………………………………………………………………………………………………………………7
2.3.1 Calpain in brain pathology…………………………………………………………………………………………………………………………………………………………………………………………………7
2.3.2 Calpain in brain physiology………………………………………………………………………………………………………………………………………………………………………………………………8
2.4 Neuronal activity induces calpain activation…………………………………………………………………………………………………………………………………………………………9
3. The CPEB family of proteins……………………………………………………………………………………………………………………………………………………………………………………………………………11
3.1 CPEB1…………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………11
3.2 CPEB1 function in neurons……………………………………………………………………………………………………………………………………………………………………………………………………………12
3.3 CPEB1 degradation…………………………………………………………………………………………………………………………………………………………………………………………………………………………………13
3.4 CPEB-like proteins, CPEB2, 3, and 4…………………………………………………………………………………………………………………………………………………………………………………14
3.5 CPEB3 function in neurons……………………………………………………………………………………………………………………………………………………………………………………………………………15
MATERIAL AND METHODS…………………………………………………………………………………………………………………………………………………………………………………………………………………………………………18
Materials………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………18
Methods……………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………27
RESULTS……………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………35
NMDA-increased EGFR synthesis requires the degradation of repressor CPEB3…………………………………………………………………………………………35
NMDAR signaling induces calpain 2-dependent cleavage of CPEB3…………………………………………………………………………………………………………………………37
CPEB3 degradation by NMDA-activated calpain 2 occurs in the cytoplasmic and synaptic compartments…………………………40
CPEB3 is cleaved by calpain 1 and calpain 2 in vitro…………………………………………………………………………………………………………………………………………………41
The calpain-cleaved CPEB3 fragment binds to RNA but fails to repress translation………………………………………………………………………42
DISCUSSION……………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………45
CPEB3-mediated translational control……………………………………………………………………………………………………………………………………………………………………………………………45
Activity-dependent cleavage of CPEB3 likely induces CPEB3-targeted RNA translation under physiological and
pathological conditions……………………………………………………………………………………………………………………………………………………………………………………………………………………………46
CPEB3 is proteolyzed by calpain 2 in cytoplasmic and synaptic compartments………………………………………………………………………………………47
Calpain-mediated cleavage modulates the function of substrate…………………………………………………………………………………………………………………………48
A genetic approach to revisit the role of calpain 1 and calpain 2 in neurons…………………………………………………………………………………49
REFERENCES……………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………52
FIGURES……………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………64

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