Cavalcante Giovanna Chaves, Brito Leonardo Miranda, Schaan Ana Paula, Ribeiro-Dos-Santos Ândrea, de Araújo Gilderlanio Santana
Laboratory of Human and Medical Genetics, Graduate Program in Genetics and Molecular Biology, Institute of Biological Sciences, Federal University of Pará, Belém 66075-110, Brazil.
Biomedicines. 2022 Apr 12;10(4):880. doi: 10.3390/biomedicines10040880.
Nuclear DNA has been the main source of genome-wide loci association in neurodegenerative diseases, only partially accounting for the heritability of Alzheimer's Disease (AD). In this context, mitochondrial DNA (mtDNA) is gaining more attention. Here, we investigated mitochondrial genes and genetic variants that may influence mild cognitive impairment and AD, through an integrative analysis including differential gene expression and mitochondrial genome-wide epistasis. We assessed the expression of mitochondrial genes in different brain tissues from two public RNA-Seq databases (GEO and GTEx). Then, we analyzed mtDNA from the ADNI Cohort and investigated epistasis regarding mitochondrial variants and levels of Aβ1-42, TAU, and Phosphorylated TAU (PTAU) from cognitively healthy controls, and both mild cognitive impairment (MCI) and AD cases. We identified multiple differentially expressed mitochondrial genes in the comparisons between cognitively healthy individuals and AD patients. We also found increased protein levels in MCI and AD patients when compared to healthy controls, as well as novel candidate networks of mtDNA epistasis, which included variants in all mitochondrially-encoded oxidative phosphorylation complexes, 12S rRNA and MT-DLOOP. Our results highlight layers of potential interactions involving mitochondrial genetics and suggest specific molecular alterations as potential biomarkers for AD.
核DNA一直是神经退行性疾病全基因组位点关联的主要来源，但仅部分解释了阿尔茨海默病（AD）的遗传力。在此背景下，线粒体DNA（mtDNA）正受到越来越多的关注。在这里，我们通过包括差异基因表达和线粒体全基因组上位性分析在内的综合分析，研究了可能影响轻度认知障碍和AD的线粒体基因和遗传变异。我们评估了来自两个公共RNA测序数据库（GEO和GTEx）的不同脑组织中线粒体基因的表达。然后，我们分析了阿尔茨海默病神经成像计划（ADNI）队列中的mtDNA，并研究了线粒体变异与认知健康对照、轻度认知障碍（MCI）和AD病例的β淀粉样蛋白1-42（Aβ1-42）、tau蛋白和磷酸化tau蛋白（PTAU）水平之间的上位性。我们在认知健康个体与AD患者的比较中鉴定出多个差异表达的线粒体基因。我们还发现，与健康对照相比，MCI和AD患者的蛋白质水平升高，以及新的mtDNA上位性候选网络，其中包括所有线粒体编码的氧化磷酸化复合物、12S核糖体RNA和线粒体D环（MT-DLOOP）中的变异。我们的结果突出了涉及线粒体遗传学的潜在相互作用层次，并提出了特定的分子改变作为AD的潜在生物标志物。
