Department of Old Age Psychiatry, Institute of Psychiatry, Psychology, & Neuroscience, King's College London, 16, De Crespigny Park, London-SE5 8AF, UK.
Institute of Mental Health, Division of Psychiatry and Applied Psychology, University of Nottingham, Nottingham-NG7 2TU, UK.
Acta Neuropsychiatr. 2020 Dec;32(6):281-292. doi: 10.1017/neu.2020.13. Epub 2020 Mar 17.
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.
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.
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.
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.
路易体痴呆（LBD）是第二大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。已经报道了几种与 LBD 相关的遗传关联，但它们的功能意义仍不确定。因此，我们旨在对所有研究 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，并为发现 LBD 的新型生物标志物和治疗靶点提供便利。
我们系统地审查了五个在线数据库（PROSPERO 方案：CRD42017080647），并使用 Ingenuity 通路分析评估了所有报告的差异表达基因（DEG）的功能意义。
我们筛选了 3809 篇文章，确定了 31 项符合条件的研究。其中，在 LBD 患者中报道了 1242 个具有统计学意义的（p < 0.05）差异表达基因（DEG），包括 70 个 microRNAs。在 LBD 中，SNCA、SNCB、PRKN、APP、RELA 和 ATXN2 的选择性剪接转录本的表达水平存在显著差异。几个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 中慢性神经炎症的证据不一致。我们的功能分析强调了 RNA 介导的基因沉默、神经调节素信号和神经营养因子在 LBD 分子病理学中的重要性。
α-突触核蛋白聚集、线粒体功能障碍、清除错误折叠蛋白的分子网络缺陷以及 RNA 介导的基因沉默导致 LBD 中的神经退行性变。需要对患有 LBD 的人的生物液体进行更大规模的纵向转录组研究，以进行 LBD 的分子亚型和分期。已确定的 DEG 的诊断生物标志物潜力和治疗前景值得进一步研究。
