目的:路易体痴呆(LBD)是第二常见的神经退行性痴呆,其发病率和死亡率高于阿尔茨海默病。已经报道了LBD的几种遗传关联,其功能含义仍不确定。因此,我们旨在对所有LBD患者的基因表达研究进行系统综述,以提高我们对LBD分子病理学的理解,并促进发现LBD的新生物标志物和治疗靶点.
方法:我们系统地回顾了五个在线数据库(PROSPERO方案:CRD42017080647),并使用IngenuityPathway分析评估了所有报告的差异表达基因(DEG)的功能含义。
结果:我们筛选了3,809篇文章,确定了31项符合条件的研究。在此,在患有LBD的人中已经报道了1,242个统计学显著(p<0.05)的DEGs,包括70个microRNA。SNCA的选择性剪接转录本的表达水平,SNCB,PRKN,APP,RELA,和ATXN2在LBD中显著不同。一些线粒体基因和参与泛素蛋白酶体系统和自噬-溶酶体途径的基因在LBD中显著下调。支持LBD慢性神经炎症的证据不一致。我们的功能分析强调了核糖核酸(RNA)介导的基因沉默的重要性,神经调节蛋白信号,和神经营养因子在LBD分子病理学中的作用。
结论:α-突触核蛋白聚集,线粒体功能障碍,清除错误折叠蛋白质的分子网络缺陷,RNA介导的基因沉默有助于LBD的神经变性。LBD的分子分型和分期需要更大的纵向转录组研究来调查LBD患者的生物体液。已识别的DEGs的诊断生物标志物潜力和治疗前景值得进一步研究。
OBJECTIVE: Lewy body dementia (LBD) is the second most prevalent neurodegenerative dementia and it causes more morbidity and mortality than Alzheimer\'s disease. Several genetic associations of LBD have been reported and their functional implications remain uncertain. Hence, we aimed to do a systematic
review of all gene expression studies that investigated people with LBD for improving our understanding of LBD molecular pathology and for facilitating discovery of novel biomarkers and therapeutic targets for LBD.
METHODS: We systematically reviewed five online databases (PROSPERO protocol: CRD42017080647) and assessed the functional implications of all reported differentially expressed genes (DEGs) using Ingenuity Pathway Analyses.
RESULTS: We screened 3,809 articles and identified 31 eligible studies. In that, 1,242 statistically significant (p < 0.05) DEGs including 70 microRNAs have been reported in people with LBD. Expression levels of alternatively spliced transcripts of SNCA, SNCB, PRKN, APP, RELA, and ATXN2 significantly differ in LBD. Several mitochondrial genes and genes involved in ubiquitin proteasome system and autophagy-lysosomal pathway were significantly downregulated in LBD. Evidence supporting chronic neuroinflammation in LBD was inconsistent. Our functional analyses highlighted the importance of ribonucleic acid (RNA)-mediated gene silencing, neuregulin signalling, and neurotrophic factors in the molecular pathology of LBD.
CONCLUSIONS: α-synuclein aggregation, mitochondrial dysfunction, defects in molecular networks clearing misfolded proteins, and RNA-mediated gene silencing contribute to neurodegeneration in LBD. Larger longitudinal transcriptomic studies investigating biological fluids of people living with LBD are needed for molecular subtyping and staging of LBD. Diagnostic biomarker potential and therapeutic promise of identified DEGs warrant further research.