Recent studies show an association of Parkin RBR E3 ubiquitin protein ligase (PARK2) copy number variations (CNVs) with attention deficit hyperactivity disorder (ADHD). The aim of our pilot study to investigate gene expression associated with PARK2 CNVs in human-derived cellular models. We investigated gene expression in fibroblasts, hiPSC and dopaminergic neurons (DNs) of ADHD PARK2 deletion and duplication carriers by qRT PCR compared with healthy and ADHD cell lines without PARK2 CNVs. The selected 10 genes of interest were associated with oxidative stress response (TP53, NQO1, and NFE2L2), ubiquitin pathway (UBE3A, UBB, UBC, and ATXN3) and with a function in mitochondrial quality control (PINK1, MFN2, and ATG5). Additionally, an exploratory RNA bulk sequencing analysis in DNs was conducted. Nutrient deprivation as a supplementary deprivation stress paradigm was used to enhance potential genotype effects. At baseline, in fibroblasts, hiPSC, and DNs, there was no significant difference in gene expression after correction for multiple testing. After nutrient deprivation in fibroblasts NAD(P)H-quinone-dehydrogenase 1 (NQO1) expression was significantly increased in PARK2 CNV carriers. In a multivariate analysis, ubiquitin C (UBC) was significantly upregulated in fibroblasts of PARK2 CNV carriers. RNA sequencing analysis of DNs showed the strongest significant differential regulation in Neurontin (NNAT) at baseline and after nutrient deprivation. Our preliminary results suggest differential gene expression in pathways associated with oxidative stress, ubiquitine-proteasome, immunity, inflammation, cell growth, and differentiation, excitation/inhibition modulation, and energy metabolism in PARK2 CNV carriers compared to wildtype healthy controls and ADHD patients.

中文翻译：

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ADHD 相关的 PARK2 拷贝数变异：关于患者来源细胞系中基因表达和补充剥夺影响的初步研究

最近的研究表明，Parkin RBR E3 泛素蛋白连接酶 ( PARK2 ) 拷贝数变异 (CNV) 与注意力缺陷多动障碍 (ADHD) 存在关联。我们初步研究的目的是研究人源细胞模型中与PARK2 CNV 相关的基因表达。我们通过 qRT PCR 与没有PARK2 CNV的健康和 ADHD 细胞系相比，研究了 ADHD PARK2缺失和重复携带者的成纤维细胞、hiPSC 和多巴胺能神经元 (DN) 中的基因表达。选定的 10 个感兴趣的基因与氧化应激反应（TP53、NQO1和NFE2L2）、泛素途径（UBE3A、UBB、UBC和ATXN3 ）相关) 并具有线粒体质量控制功能（PINK1、MFN2和ATG5）。此外，还进行了 DN 中的探索性 RNA 批量测序分析。营养剥夺作为补充剥夺应激范例被用来增强潜在的基因型效应。在基线时，在成纤维细胞、hiPSC 和 DN 中，多次测试校正后基因表达没有显着差异。在成纤维细胞营养剥夺后， PARK2 CNV 携带者的 NAD(P)H-醌脱氢酶 1 ( NQO1 ) 表达显着增加。在多变量分析中，泛素 C ( UBC ) 在PARK2的成纤维细胞中显着上调CNV载体。DN 的 RNA 测序分析显示，在基线和营养剥夺后，Neurontin ( NNAT ) 中的显着差异调节最强。我们的初步结果表明，与野生型健康对照和 ADHD 患者相比， PARK2 CNV 携带者在与氧化应激、泛素-蛋白酶体、免疫、炎症、细胞生长和分化、激发/抑制调节和能量代谢相关的通路中存在差异基因表达。