Nuclear speckle specific hnRNP D-like prevents age- and AD-related cognitive decline by modulating RNA splicing
| العنوان: | Nuclear speckle specific hnRNP D-like prevents age- and AD-related cognitive decline by modulating RNA splicing |
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| المؤلفون: | Xiaolin Ma, Huaxi Xu, Jin Ye, Juan Zhang, Qingyang Zhang, Yingjun Zhao, Hongda Liu, Keqiang He, Chao Wang, Ji Yuan, Wei Zhang, Xiaohui Li, Qiang Liu |
| المصدر: | Molecular Neurodegeneration, Vol 16, Iss 1, Pp 1-19 (2021) Molecular Neurodegeneration |
| بيانات النشر: | BMC, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Spliceosome, Aging, RNA Splicing, Alzheimer’s disease (AD), Biology, Heterogeneous ribonucleoprotein particle, Heterogeneous-Nuclear Ribonucleoproteins, Cellular and Molecular Neuroscience, Mice, Cognition, Downregulation and upregulation, Alzheimer Disease, hnRNP DL, Gene expression, Nuclear speckles, Animals, snRNP, Cognitive Dysfunction, RC346-429, Molecular Biology, Alternative splicing, RC952-954.6, RNA, Cell biology, Geriatrics, RNA splicing, Neurology (clinical), Neurology. Diseases of the nervous system, Research Article |
| الوصف: | BackgroundAberrant alternative splicing plays critical role in aging and age-related diseases. Heterogeneous nuclear ribonucleoproteins (hnRNPs) reportedly regulate RNA splicing process. Whether and how hnRNPs contribute to age-related neurodegenerative diseases, especially Alzheimer’s disease (AD), remain elusive.MethodsImmunoblotting and immunostaining were performed to determine expression patterns and cellular/subcellular localization of the long isoform of hnRNP D-like (L-DL), which is a hnRNP family member, in mouse hippocampus. Downregulation of L-DL in WT mice was achieved by AAV-mediated shRNA delivery, followed by memory-related behavioural tests. L-DL interactome was analysed by affinity-precipitation and mass spectrometry. Alternative RNA splicing was measured by RNA-seq and analyzed by bioinformatics-based approaches. Downregulation and upregulation of L-DL in APP/PS1 mice were performed using AAV-mediated transduction.ResultsWe show that L-DL is specifically localized to nuclear speckles. L-DL levels are decreased in the hippocampus of aged mouse brains and downregulation of L-DL impairs cognition in mice. L-DL serves as a structural component to recruit other speckle proteins, and regulates cytoskeleton- and synapse-related gene expression by altering RNA splicing. Mechanistically, these splicing changes are modulated via L-DL-mediated interaction of SF3B3, a core component of U2 snRNP, and U2AF65, a U2 spliceosome protein that guides U2 snRNP’s binding to RNA. In addition, L-DL levels are decreased in APP/PS1 mouse brains. While downregulation of L-DL deteriorates memory deficits and overexpression of L-DL improves cognitive function in AD mice, by regulating the alternative splicing and expression of synaptic geneCAMKV.ConclusionsOur findings define a molecular mechanism by which hnRNP L-DL regulates alternative RNA splicing, and establish a direct role for L-DL in AD-related synaptic dysfunction and memory decline. |
| اللغة: | English |
| تدمد: | 1750-1326 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2ecf1efc262f6c7d55e912eb07700b18Test https://doaj.org/article/653dd67fd7004fd4b10f2c4a1e56cfc2Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....2ecf1efc262f6c7d55e912eb07700b18 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 17501326 |
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