An increase in VGF expression through a rapid, transcription-independent, autofeedback mechanism improves cognitive function.
An increase in VGF expression through a rapid, transcription-independent, autofeedback mechanism improves cognitive function.
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通过快速、转录独立的自动反馈机制增加 VGF 表达，改善认知功能
DOI：
10.1038/s41398-021-01489-2
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发表时间：
2021-07-08
影响因子：
6.8
通讯作者：
Ye X
中科院分区：
文献类型：
--
作者：
Lin WJ;Zhao Y;Li Z;Zheng S;Zou JL;Warren NA;Bali P;Wu J;Xing M;Jiang C;Tang Y;Salton SR;Ye X
致密核心囊泡（DCV）释放的神经肽调节神经元的活动，并在认知功能和情绪中起着关键作用。颗粒蛋白家族被认为是DCV生物发生和DCV货物分子释放的主要调节剂。VGF蛋白（nonacronymic）是一种分泌的神经肽前体，也属于扩展的颗粒蛋白家族，其表达先前已被证明在大脑中由海马依赖性学习诱导，并且其下调与神经退行性疾病如阿尔茨海默病和其他情绪障碍有机械联系。目前，Vgf和其他颗粒蛋白mRNA的翻译效率的变化是否与学习相关的神经活动相关并受其调节，在很大程度上仍然未知。在这里，我们表明，无论是上下文的恐惧记忆训练或TLQP-62，来自C-末端区域的VGF前体肽的管理，急剧增加的翻译VGF和其他颗粒蛋白，如CgB和Scg 2，通过mTOR依赖的信号通路在mRNA表达的可测量的增加的情况下。基于荧光素酶的报告基因分析证实VgfmRNA的3′非翻译区（3′UTR）抑制VGF的翻译。因此，内源性VgfmRNA 3′UTR的截短导致VGF蛋白在培养的原代神经元和表达由修饰的Vgf基因编码的3′ UTR截短突变体的小鼠中的敲除脑组织中的表达显著增加。重要的是，Vgf 3 ′ UTR截短的小鼠表现出增强的记忆能力和减少的焦虑和抑郁样行为。因此，我们的研究结果揭示了一个快速的，转录独立的诱导VGF和其他颗粒蛋白的学习后，触发的VGF衍生肽TLQP-62。我们的研究结果表明，颗粒蛋白家族蛋白合成的快速、正向前馈增加可能是补充响应神经元激活而释放的DCV货物分子的一般机制，并且对于记忆功能和情绪稳定至关重要。
The release of neuropeptides from dense core vesicles (DCVs) modulates neuronal activity and plays a critical role in cognitive function and emotion. The granin family is considered a master regulator of DCV biogenesis and the release of DCV cargo molecules. The expression of the VGF protein (nonacronymic), a secreted neuropeptide precursor that also belongs to the extended granin family, has been previously shown to be induced in the brain by hippocampus-dependent learning, and its downregulation is mechanistically linked to neurodegenerative diseases such as Alzheimer’s disease and other mood disorders. Currently, whether changes in translational efficiency ofVgfand other granin mRNAs may be associated and regulated with learning associated neural activity remains largely unknown. Here, we show that either contextual fear memory training or the administration of TLQP-62, a peptide derived from the C-terminal region of the VGF precursor, acutely increases the translation of VGF and other granin proteins, such as CgB and Scg2, via an mTOR-dependent signaling pathway in the absence of measurable increases in mRNA expression. Luciferase-based reporter assays confirmed that the 3′-untranslated region (3′UTR) of theVgfmRNA represses VGF translation. Consistently, the truncation of the endogenousVgfmRNA 3′UTR results in substantial increases in VGF protein expression both in cultured primary neurons and in brain tissues from knock in mice expressing a 3′UTR-truncation mutant encoded by the modifiedVgfgene. Importantly,Vgf3′UTR-truncated mice exhibit enhanced memory performance and reduced anxiety- and depression-like behaviors. Our results therefore reveal a rapid, transcription-independent induction of VGF and other granin proteins after learning that are triggered by the VGF-derived peptide TLQP-62. Our findings suggest that the rapid, positive feedforward increase in the synthesis of granin family proteins might be a general mechanism to replenish DCV cargo molecules that have been released in response to neuronal activation and is crucial for memory function and mood stability.
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影响因子：
2.9
作者：
FLOOD, JF;BENNETT, EL;ROSENZWEIG, MR
通讯作者：
ROSENZWEIG, MR
DOI：
10.1523/jneurosci.3145-08.2008
发表时间：
2008-09-24
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Bozdagi O;Rich E;Tronel S;Sadahiro M;Patterson K;Shapiro ML;Alberini CM;Huntley GW;Salton SR
通讯作者：
Salton SR
影响因子：
2.7
作者：
Bekinschtein, Pedro;Katche, Cynthia;Medina, Jorge H.
通讯作者：
Medina, Jorge H.
影响因子：
16.2
作者：
Hahm, S;Mizuno, TM;Salton, SRJ
通讯作者：
Salton, SRJ
影响因子：
3.1
作者：
FORSSPETTER, S;DANIELSON, P;SUTCLIFFE, JG
通讯作者：
SUTCLIFFE, JG