Pin1 in Synaptic Plasticity and Translation

突触可塑性和翻译中的 Pin1

• 批准号: 7860521
• 负责人: James S Malter
• 金额: $ 37.13万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7860521
• 关键词: Ablation; Alzheimer' s Disease; Anisomycin; Apoptotic; Behavioral; Binding; Binding Proteins; Biochemical; Brain; C-terminal; Catabolism; Cell Nucleus; Cells; Chemicals; Cyclic AMP-Dependent Protein Kinases; Cytoplasm; Data; Dendrites; Dendritic Spines; Development; Enzymes; Genetic; Genetic Transcription; Glutamate Receptor; Glutamates; Hippocampus (Brain); Human; Learning; Location; Long-Term Potentiation; Maintenance; Mediating; Memory; Messenger RNA; Microtubule-Associated Proteins; Mitotic; Modification; Molecular; Mus; N-terminal; Neurons; Peptides; Peptidylprolyl Isomerase; Phosphorylation; Phosphotransferases; Play; Preparation; Process; Protein Biosynthesis; Protein Dephosphorylation; Protein Synthesis Induction; Proteins; Regulation; Role; Signal Transduction; Site; Slice; Specificity; Synapses; Synaptic plasticity; Translations; Western Blotting; age related neurodegeneration; chemical genetics; human FRAP1 protein; information processing; inhibitor/antagonist; neuronal cell body; protein function; protein kinase C zeta; seryl-proline; transcription factor

Consolidation of synaptic plasticity and memory requires biochemical alterations in the molecular composition of the synapse. The process of consolidation involves multiple processes including local translation of preexisting, dendritic mRNAs and results in changes in synaptic efficacy and storage of new memories that persist from days to years. While a few of the effectors of memory have been identified, relatively little is understood about how these molecules govern the induction of long-term forms of synaptic plasticity. We now show that Pin1, a cis-trans peptidyl-prolyl isomerase with specificity for Ser-Pro or Thr-Pro peptide bonds, plays a key role in synaptic plasticity. Pin1 is present in dendrites and spines and under basal conditions, suppresses dendritic protein synthesis. Glutamate signaling inactivates Pin1, leading to increased translation of many proteins including the plasticity related kinases PKMand PKC In the genetic absence of Pin1, hippocampal L-LTP is increased as are the levels of PKMand PKC. PKMand PKCactivity were necessary to maintain the suppression of Pin1 activity after glutamate signaling as well as dendritic translation. These data suggest glutamatergic signaling inhibits Pin1 which leads to the translation of PKM and PKC. Once produced, these kinases then support on-going dendritic translation partially by suppressing Pin1. As such our aims are to determine 1) the role of PKMin regulating Pin1 and 2) further characterize PKM function by identifying its downstream targets through chemical-genetics.

突触可塑性和记忆的巩固需要突触分子组成的生化改变。巩固的过程涉及多个过程，包括预先存在的树突状mRNA的局部翻译，并导致突触功效的变化和持续数天至数年的新记忆的储存。虽然已经确定了一些记忆效应物，但对这些分子如何控制突触可塑性的长期形式的诱导的了解相对较少。我们现在表明，Pin 1，一个顺-反肽基脯氨酰异构酶与Ser-Pro或Thr-Pro肽键的特异性，在突触可塑性中起着关键作用。Pin 1存在于树突和棘中，并且在基础条件下抑制树突蛋白质合成。谷氨酸信号使Pin 1失活，导致许多蛋白质的翻译增加，包括可塑性相关激酶PKM β和PKC β。在Pin 1基因缺失的情况下，海马L-LTP增加，PKM β和PKC β的水平也增加。PKM激酶和PKC激酶活性是维持谷氨酸信号传导后Pin 1活性抑制以及树突翻译所必需的。这些数据表明谷氨酸能信号传导抑制Pin 1，从而导致PKM和PKC的翻译。一旦产生，这些激酶然后通过抑制Pin 1部分地支持正在进行的树突翻译。因此，我们的目标是确定1）PKM激酶在调节Pin 1中的作用和2）通过化学遗传学鉴定其下游靶标来进一步表征PKM激酶功能。

项目成果

Pin1 and PKMzeta sequentially control dendritic protein synthesis.

Pin1 和 PKMzeta 依次控制树突蛋白的合成。

• DOI: 10.1126/scisignal.2000451
• 发表时间: 2010
• 期刊: Science signaling
• 影响因子: 7.3
• 作者: Westmark,PamelaR;Westmark,CaraJ;Wang,SuQing;Levenson,Jonathan;O'Riordan,KennethJ;Burger,Corinna;Malter,JamesS
• 通讯作者: Malter,JamesS

Alzheimer's disease and Down syndrome rodent models exhibit audiogenic seizures.

阿尔茨海默病和唐氏综合症啮齿动物模型表现出听源性癫痫发作。

• DOI: 10.3233/jad-2010-100087
• 发表时间: 2010
• 期刊: Journal of Alzheimer's disease : JAD
• 作者: Westmark,CaraJ;Westmark,PamelaR;Malter,JamesS
• 通讯作者: Malter,JamesS