Presenilin 1 mutation likely contributes to U1 small nuclear RNA dysregulation and Alzheimer's disease–like symptoms
| Autor: | Xinxin Xu, Yongwang Zhang, Tao Zhang, Yingchun Shang, Zhiqiang Dong, Zhi Cheng, Zhanqiang Du, Xinyi Lu |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Aging genetic processes information science Gene Expression In situ hybridization environment and public health Amyloid beta-Protein Precursor 03 medical and health sciences 0302 clinical medicine Alzheimer Disease RNA Small Nuclear Gene expression Presenilin-1 medicine Amyloid precursor protein Animals Binding site Cells Cultured Neurons Amyloid beta-Peptides biology urogenital system General Neuroscience Neurodegeneration Intron Brain medicine.disease Introns Up-Regulation Cell biology Mice Inbred C57BL 030104 developmental biology Mutation RNA splicing health occupations biology.protein Neurology (clinical) Geriatrics and Gerontology 030217 neurology & neurosurgery Small nuclear RNA Developmental Biology |
| Zdroj: | Neurobiology of Aging. 100:1-10 |
| ISSN: | 0197-4580 |
| DOI: | 10.1016/j.neurobiolaging.2020.12.015 |
| Popis: | Previous studies showed that U1 small nuclear RNA (snRNA) was selectively enriched in the brain of individuals with familial Alzheimer's disease (AD), resulting in widespread changes in RNA splicing. Our study further reported that presenilin-1 (PSEN1) induced an increase in U1 snRNA expression, accompanied by changed amyloid precursor protein expression, β-amyloid level, and cell death in SH-SY5Y cells. However, the effect of U1 snRNA overexpression on learning and memory is still unclear. In the present study, we found that neuronal U1 snRNA overexpression could generate U1 snRNA aggregates in the nuclear, accompanied by the widespread alteration of RNA splicing, resulting in the impairments of synaptic plasticity and spatial memory. In addition, more U1 snRNAs is bound to the intron binding sites accompanied by an increased intracellular U1 snRNA level. This suggests that U1 snRNA overexpression regulates RNA splicing and gene expression in neurons by manipulating the recruitment of the U1 snRNA to the nascent transcripts. Using in situ hybridization staining of human central nervous system-type neurons, we identified nuclear aggregates of U1 snRNA in neurons by upregulating the U1 snRNA level. Quantitative polymerase chain reaction analysis showed U1 snRNA accumulation in the insoluble fraction of neurons with PSEN1 mutation neurons rather than other types of U snRNAs. These results show an independent function of U1 snRNA in regulating RNA splicing, suggesting that aberrant RNA processing may mediate neurodegeneration induced by PSEN1 mutation. |
| Databáze: | OpenAIRE |
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