ADHD-associated PARK2 copy number variants: A pilot study on gene expression and effects of supplementary deprivation in patient-derived cell lines
Radtke F, Palladino VS, McNeill RV, Chiocchetti AG, Haslinger D, Leyh M, Gersic D, Frank M, Grünewald L, Klebe S, Brüstle O, Günther K, Edenhofer F, Kranz TM, Reif A, Kittel-Schneider S (2022)
Publication Type: Journal article
Publication year: 2022
Journal
Book Volume: 189
Pages Range: 257-270
Journal Issue: 7-8
DOI: 10.1002/ajmg.b.32918
Abstract
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.
Involved external institutions
Universitätsklinikum Würzburg
Germany (DE)
Universitätsklinikum Frankfurt am Main (KGU)
Germany (DE)
Universitätsklinikum Essen
Germany (DE)
Rheinische Friedrich-Wilhelms-Universität Bonn
Germany (DE)
Leopold-Franzens-Universität Innsbruck / University of Innsbruck
Austria (AT)
Germany (DE)
Universitätsklinikum Frankfurt am Main (KGU)
Germany (DE)
Universitätsklinikum Essen
Germany (DE)
Rheinische Friedrich-Wilhelms-Universität Bonn
Germany (DE)
Leopold-Franzens-Universität Innsbruck / University of Innsbruck
Austria (AT)
How to cite
APA:
Radtke, F., Palladino, V.S., McNeill, R.V., Chiocchetti, A.G., Haslinger, D., Leyh, M.,... Kittel-Schneider, S. (2022). ADHD-associated PARK2 copy number variants: A pilot study on gene expression and effects of supplementary deprivation in patient-derived cell lines. American Journal of Medical Genetics Part B-Neuropsychiatric Genetics, 189(7-8), 257-270. https://doi.org/10.1002/ajmg.b.32918
MLA:
Radtke, Franziska, et al. "ADHD-associated PARK2 copy number variants: A pilot study on gene expression and effects of supplementary deprivation in patient-derived cell lines." American Journal of Medical Genetics Part B-Neuropsychiatric Genetics 189.7-8 (2022): 257-270.
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