ADHD‐associated PARK2 copy number variants: A pilot study on gene expression and effects of supplementary deprivation in patient‐derived cell lines

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.

hiPSC-derived cortical neurons from ADHD individuals reveal dysregulated glutamatergic development

“…Two of these studies are our own work, using hiPSC-derived dopaminergic neurons to investigate metabolic differences in ADHD patient carriers of parkin (PARK2) copy number variables. We found changes in PARK2 gene and protein expression, ATP production and basal oxygen consumption rate in CNV carriers 26 , along with altered transcriptomics 27 . A recent study by Yde Ohki et al was able to identify proliferation rate alterations in hiPSC-derived neural stem cells derived from male child and adolescent ADHD patients 28 .…”

Prenatal Chromosomal Microarray Analysis: Does Increased Resolution Equal Increased Yield?

“…In one case, a 230 Kb duplication of 6q26 was identified that included the PARK2 gene. CNVs in this gene have been reported as a risk factor for ADHD [ 36 ]. The finding was maternally inherited and, as such, was classified as a VUS.…”

From attention-deficit hyperactivity disorder to sporadic Alzheimer’s disease—Wnt/mTOR pathways hypothesis

“…Both may be a result of long-lasting alterations in neurodevelopmental processes, but may also be one of the etiopathogenic factors. Partially linked with mitochondrial dysfunction, the energy metabolism imbalance in ADHD has been discussed as a possible source of neurodevelopmental delays ( Cannon Homaei et al, 2022 ; Foschiera et al, 2022 ; Radtke et al, 2022 ). Cerebral glucose hypometabolism has been found in childhood-onset adult ADHD patients ( Zametkin et al, 1990 ), however, this may also be a consequence of deficits in impulse control leading to metabolic syndrome ( di Girolamo et al, 2022 ).…”