死后路易体痴呆脑的转录组选择性剪接和转录水平差异表达分析。

IF 2.6 4区 医学 Q3 NEUROSCIENCES
Thomas R Goddard, Keeley J Brookes, Kevin Morgan, Dag Aarsland, Paul Francis, Anto P Rajkumar
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引用次数: 0

摘要

路易体痴呆(LBD)是第二常见的痴呆。有几个基因与LBD相关,但对它们在LBD病理生理中的作用知之甚少。每个基因可能转录多个RNA, LBD大脑有广泛的RNA剪接失调。因此,我们完成了首个死后LBD大脑的转录组全转录水平差异表达分析,以获得更多LBD分子病理的见解,这对于促进发现新的LBD治疗靶点和生物标志物至关重要。我们完成了对病理证实的LBD患者(LBD = 14;对照组= 7)使用鲑鱼。我们使用edgeR鉴定了差异表达转录本(DET),并使用DAVID研究了它们的功能含义。我们使用DRIMseq进行转录组范围内的选择性剪接分析。在benjamin - hochberg错误发现率(FDR)校正(5%)后,我们发现ACC中有74个DET, DLPFC中有96个DET。LBD脑ACC和DLPFC中分别有135个和98个fdr校正的选择性剪接基因。已确定的DET可能通过改变DNA修复、细胞凋亡、神经可塑性、蛋白质磷酸化和RNA转录调节来促进LBD病理。我们证实在LBD大脑中广泛存在选择性剪接和慢性神经炎症的缺失。转录水平差异表达分析可以揭示基因水平表达分析无法检测到的特异性DET。已鉴定DET的治疗和诊断生物标志物潜力,特别是来自TMEM18、MICB、MPO和GABRB3的生物标志物,值得进一步研究。未来基于LBD血液的生物标志物研究应优先测量小细胞外囊泡中已识别的DET。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Transcriptome-wide alternative splicing and transcript-level differential expression analysis of post-mortem Lewy body dementia brains.

Lewy body dementias (LBD) are the second most common dementia. Several genes have been associated with LBD, but little is known about their contributions to LBD pathophysiology. Each gene may transcribe multiple RNA, and LBD brains have extensive RNA splicing dysregulation. Hence, we completed the first transcriptome-wide transcript-level differential expression analysis of post-mortem LBD brains for gaining more insights into LBD molecular pathology that are essential for facilitating discovery of novel therapeutic targets and biomarkers for LBD. We completed transcript-level quantification of next-generation RNA-sequencing data from post-mortem anterior cingulate (ACC) and dorsolateral prefrontal cortices (DLPFC) of people with pathology-verified LBD (LBD = 14; Controls = 7) using Salmon. We identified differentially expressed transcripts (DET) using edgeR and investigated their functional implications using DAVID. We performed transcriptome-wide alternative splicing analysis using DRIMseq. We identified 74 DET in ACC and 96 DET in DLPFC after Benjamini-Hochberg false discovery rate (FDR) correction (5%). There were 135 and 98 FDR-corrected alternatively spliced genes in ACC and DLPFC of LBD brains, respectively. Identified DET may contribute to LBD pathology by altering DNA repair, apoptosis, neuroplasticity, protein phosphorylation, and regulation of RNA transcription. We confirm widespread alternative splicing and absence of chronic neuroinflammation in LBD brains. Transcript-level differential expression analysis can reveal specific DET that cannot be detected by gene-level expression analyses. Therapeutic and diagnostic biomarker potential of identified DET, especially those from TMEM18, MICB, MPO, and GABRB3, warrant further investigation. Future LBD blood-based biomarker studies should prioritise measuring the identified DET in small extracellular vesicles.

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来源期刊
Acta Neuropsychiatrica
Acta Neuropsychiatrica NEUROSCIENCES-PSYCHIATRY
自引率
5.30%
发文量
30
期刊介绍: Acta Neuropsychiatrica is an international journal focussing on translational neuropsychiatry. It publishes high-quality original research papers and reviews. The Journal''s scope specifically highlights the pathway from discovery to clinical applications, healthcare and global health that can be viewed broadly as the spectrum of work that marks the pathway from discovery to global health.
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