A Novel Alzheimer-Associated SNP in Tmp21 Increases Amyloidogenesis
Autor: | Kelley Bromley-Brits, Xiaojie Zhang, Kun Xia, Yili Wu, Weihong Song, Shengchun Liu, Fang Cai |
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Rok vydání: | 2017 |
Předmět: |
Male
0301 basic medicine Amyloid Nucleocytoplasmic Transport Proteins Neuroscience (miscellaneous) Single-nucleotide polymorphism Biology Polymorphism Single Nucleotide Pathogenesis 03 medical and health sciences Cellular and Molecular Neuroscience Alzheimer Disease Gene expression Humans SNP Allele Aged Genetic association Aged 80 and over Genetics Amyloid beta-Peptides Intron Membrane Proteins Molecular biology 030104 developmental biology Neurology RNA splicing Female |
Zdroj: | Molecular Neurobiology. 55:1862-1870 |
ISSN: | 1559-1182 0893-7648 |
Popis: | Recent studies suggest that TMP21 is a selective modulator of γ-secretase and its dysregulation affects APP processing, leading to increased Aβ generation. However, the genetic association between Tmp21 and Alzheimer's disease (AD) remains elusive. In this study, we identified that a novel single-nucleotide polymorphism (SNP) rs12435391 (IVS4-28T>C) in intron 4 of Tmp21 was genetically associated with AD. We found that allele C of the SNP rs12435391 did not affect splicing site recognition, but it significantly increased TMP21 gene expression. The stability of Tmp21 pre-mRNA and the transcription of Tmp21 were not affected by allele C of the SNP rs12435391. However, allele C of the SNP rs12435391 significantly increased the splicing efficiency of Tmp21 pre-mRNA, leading to the elevation of mature mRNA. Furthermore, allele C of the SNP rs12435391 significantly reduced C83 level and increased Aβ generation. Taken together, our study suggests that TMP21 is genetically associated with Alzheimer's disease, with the novel Tmp21 SNP as a risk factor for Alzheimer's pathogenesis. |
Databáze: | OpenAIRE |
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