An increase in VGF expression through a rapid, transcription-independent, autofeedback mechanism improves cognitive function
| Autor: | Mengdan Xing, Zhe Li, Xiaojing Ye, Stephen R.J. Salton, Jin-lin Zou, Purva Bali, Yamei Tang, Wei-Jye Lin, Cheng Jiang, Noël A. Warren, Shuyu Zheng, Jingru Wu, Yan Zhao |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Translational efficiency Neuropeptide Neurosciences. Biological psychiatry. Neuropsychiatry Molecular neuroscience Hippocampus Article Mice 03 medical and health sciences Cellular and Molecular Neuroscience Cognition 0302 clinical medicine Downregulation and upregulation Memory Gene knockin Animals Biological Psychiatry Neurons Messenger RNA Chemistry Granin Translation (biology) Cell biology Psychiatry and Mental health 030104 developmental biology Signal transduction Peptides 030217 neurology & neurosurgery RC321-571 |
| Zdroj: | Translational Psychiatry, Vol 11, Iss 1, Pp 1-11 (2021) Translational Psychiatry |
| ISSN: | 2158-3188 |
| Popis: | 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 of Vgf and 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 the Vgf mRNA represses VGF translation. Consistently, the truncation of the endogenous Vgf mRNA 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 modified Vgf gene. Importantly, Vgf 3′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. |
| Databáze: | OpenAIRE |
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