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ADHD-associated PARK2 copy number variants: A pilot study on gene expression and effects of supplementary deprivation in patient-derived cell lines.
Radtke, Franziska; Palladino, Viola Stella; McNeill, Rhiannon V; Chiocchetti, Andreas G; Haslinger, Denise; Leyh, Matthias; Gersic, Danijel; Frank, Markus; Grünewald, Lena; Klebe, Stephan; Brüstle, Oliver; Günther, Katharina; Edenhofer, Frank; Kranz, Thorsten M; Reif, Andreas; Kittel-Schneider, Sarah.
Afiliación
  • Radtke F; Department of Child and Adolescent Psychiatry, Psychotherapy and Psychosomatic Medicine, University Hospital, University of Würzburg, Würzburg, Germany.
  • Palladino VS; Department of Psychiatry, Psychotherapy and Psychosomatic Medicine, University Hospital, Goethe University, Frankfurt, Germany.
  • McNeill RV; Department of Psychiatry, Psychotherapy and Psychosomatic Medicine, University Hospital, University of Würzburg, Würzburg, Germany.
  • Chiocchetti AG; Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital, Goethe University, Frankfurt, Germany.
  • Haslinger D; Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital, Goethe University, Frankfurt, Germany.
  • Leyh M; Department of Psychiatry, Psychotherapy and Psychosomatic Medicine, University Hospital, Goethe University, Frankfurt, Germany.
  • Gersic D; Department of Psychiatry, Psychotherapy and Psychosomatic Medicine, University Hospital, University of Würzburg, Würzburg, Germany.
  • Frank M; Department of Psychiatry, Psychotherapy and Psychosomatic Medicine, University Hospital, University of Würzburg, Würzburg, Germany.
  • Grünewald L; Department of Psychiatry, Psychotherapy and Psychosomatic Medicine, University Hospital, Goethe University, Frankfurt, Germany.
  • Klebe S; Department of Neurology, University Hospital Essen, Essen, Germany.
  • Brüstle O; Institute of Reconstructive Neurobiology, University of Bonn, Bonn, Germany.
  • Günther K; Department of Genomics, Stem Cell Biology and Regenerative Medicine, Institute of Molecular Biology & CMBI, University of Innsbruck, Innsbruck, Austria.
  • Edenhofer F; Department of Genomics, Stem Cell Biology and Regenerative Medicine, Institute of Molecular Biology & CMBI, University of Innsbruck, Innsbruck, Austria.
  • Kranz TM; Department of Psychiatry, Psychotherapy and Psychosomatic Medicine, University Hospital, Goethe University, Frankfurt, Germany.
  • Reif A; Department of Psychiatry, Psychotherapy and Psychosomatic Medicine, University Hospital, Goethe University, Frankfurt, Germany.
  • Kittel-Schneider S; Department of Psychiatry, Psychotherapy and Psychosomatic Medicine, University Hospital, Goethe University, Frankfurt, Germany.
Am J Med Genet B Neuropsychiatr Genet ; 189(7-8): 257-270, 2022 10.
Article en En | MEDLINE | ID: mdl-35971782
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Trastorno por Déficit de Atención con Hiperactividad / Ubiquitina-Proteína Ligasas / Variaciones en el Número de Copia de ADN Tipo de estudio: Risk_factors_studies Límite: Humans Idioma: En Revista: Am J Med Genet B Neuropsychiatr Genet Asunto de la revista: GENETICA MEDICA / NEUROLOGIA / PSIQUIATRIA Año: 2022 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Trastorno por Déficit de Atención con Hiperactividad / Ubiquitina-Proteína Ligasas / Variaciones en el Número de Copia de ADN Tipo de estudio: Risk_factors_studies Límite: Humans Idioma: En Revista: Am J Med Genet B Neuropsychiatr Genet Asunto de la revista: GENETICA MEDICA / NEUROLOGIA / PSIQUIATRIA Año: 2022 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos