Liu Qiang/Xu Huaxi team collaborated to discover a new mechanism for RNA-binding protein to regulate brain aging and Alzheimer's disease

RNA binding protein is a class of molecules involved in the regulation of gene expression at the post-transcriptional level
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hnRNP protein, also known as heterogeneous nuclear ribonucleoprotein, is an important type of RNA binding protein
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The RNA-binding protein family can participate in multiple RNA metabolic processes, including the stability of mRNA and the nucleation of mRNA, and its most widely studied function is to participate in the splicing process of RNA
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Some studies have shown that extensive changes in RNA splicing occur in the aging brain, and these splicing changes directly or indirectly affect the level of synaptic proteins and synaptic function
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At the same time, the brain of Alzheimer's disease (AD) also undergoes extensive changes in RNA splicing.
These splicing changes lead to changes in the deposition of pathological proteins, which in turn have an impact on the pathology of the disease
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Nuclear Speckle is the substructure of the cell nucleus and the main place where RNA splicing occurs
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A number of identified hnRNP family proteins involved in the regulation of RNA splicing are expressed and distributed in the nuclear speckle
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The hippocampus of the brain (hippocampus) is the brain area with active high-level cognitive functions, responsible for the generation of high-level cognitive functions such as spatial memory and episodic memory
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The hippocampus brain area is very sensitive to aging and other stress damage, and this brain area is also one of the brain areas most severely affected by aging
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The aging process is usually accompanied by cognitive dysfunction.
In all brain areas, the cognitive function based on the hippocampus appears to decline in the early stage.
At the same time, it is also one of the brain areas that are seriously damaged in the pathological process of Alzheimer's disease
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The key scientific question to be solved is whether hnRNP family proteins can participate in the pathological process of brain aging and AD by regulating RNA splicing, especially in the regulation of hippocampal-based cognitive functions
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On September 23, 2021, Professor Liu Qiang from University of Science and Technology of China and Professor Xu Huaxi from Xiamen University jointly published a research paper on Molecular Neurodegeneration Nuclear speckle specific hnRNP D-Like prevents age- and AD-related cognitive decline by modulating RNA splicing, the article reveals The RNA-binding protein hnRNP D-Like participates in a new mechanism that regulates brain aging and Alzheimer's disease by regulating the RNA alternative splicing process of neurons
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The researchers first identified two spliceosome forms of hnRNP D-Like (DL) in the brain: Long isoform of hnRNP DL (L-DL) and Short isoform of hnRNP DL (S-DL)
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Through screening, it was found that L-DL showed an age-dependent down-regulation in the hippocampal brain regions of mice, while S-DL did not change significantly
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Through immunofluorescence method, it was found that L-DL was specifically located in the nuclear speckle of neurons
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To further confirm the regulatory function of L-DL in the aging brain, the researchers specifically knocked down L-DL in the hippocampus of young wild-type mice and found that these mice showed significant cognitive dysfunction
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Proteomics analysis shows that L-DL interacts with multiple nuclear speckle core proteins, which further supports the nuclear speckle positioning of L-DL
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In L-DL-deficient cells, nuclear speckle undergoes significant structural changes, suggesting that L-DL may be the backbone protein of nuclear speckle and participate in maintaining its structural integrity
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In terms of mechanism, it is found that L-DL interacts with U2 snRNP in the nucleus and related to the splicing process, thereby affecting the alternative splicing process of RNA
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Further RNA splicing analysis showed that L-DL participates in the splicing process of multiple synapses and cytoskeleton-related genes, thereby affecting the expression levels of synaptic proteins and skeletal proteins, and then affecting synaptic function
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In addition to participating in aging and aging-related cognitive decline by regulating the splicing process of RNA, L-DL can also participate in the pathological process of AD by regulating the splicing process of RNA
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The CAMKV gene has been shown to play an important role in neurosynaptic plasticity and the process of learning and memory
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Researchers found that knocking down L-DL in AD model mice (APP/PS1) can change the alternative splicing form of CAMKV and significantly reduce the level of CAMKV; while overexpression of L-DL can enhance the expression of CAMKV
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By regulating a series of splicing processes, the levels of synaptic proteins and related receptors, including synaptic proteins PSD95, SNAP25, and synaptic receptor NR2B, are ultimately affected, thereby affecting the cognitive function of model mice
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In summary, this study reports an RNA-binding protein hnRNP DL and how it participates in the regulation of brain aging and the process of Alzheimer’s disease through the regulation of RNA splicing process, in order to further understand the molecular mechanism of aging brain and aging-related neurodegeneration.
The pathogenesis of sexual diseases provides important clues and new targets for the treatment of aging-related neurodegenerative diseases
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The first author of this study is Zhang Qingyang, a PhD student in Liu Qiang's research group.
Professor Liu Qiang and Professor Xu Huaxi are the co-corresponding authors of this article.
The research of this project
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 Original link: https://molecularneurodegeneration.
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