Energy Metabolism Disturbances in Cell Models of PARK2 CNV Carriers with ADHD

Abstract

The main goal of the present study was the identification of cellular phenotypes in attention-deficit-/hyperactivity disorder (ADHD) patient-derived cellular models from carriers of rare copy number variants (CNVs) in the PARK2 locus that have been previously associated with ADHD. Human-derived fibroblasts (HDF) were cultured and human-induced pluripotent stem cells (hiPSC) were reprogrammed and differentiated into dopaminergic neuronal cells (mDANs). A series of assays in baseline condition and in different stress paradigms (nutrient deprivation, carbonyl cyanide m-chlorophenyl hydrazine (CCCP)) focusing on mitochondrial function and energy metabolism (ATP production, basal oxygen consumption rates, reactive oxygen species (ROS) abundance) were performed and changes in mitochondrial network morphology evaluated. We found changes in PARK2 CNV deletion and duplication carriers with ADHD in PARK2 gene and protein expression, ATP production and basal oxygen consumption rates compared to healthy and ADHD wildtype control cell lines, partly differing between HDF and mDANs and to some extent enhanced in stress paradigms. The generation of ROS was not influenced by the genotype. Our preliminary work suggests an energy impairment in HDF and mDAN cells of PARK2 CNV deletion and duplication carriers with ADHD. The energy impairment could be associated with the role of PARK2 dysregulation in mitochondrial dynamics.

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

“…and our finding might also point to a role in ADHD. As NNMT plays a role in glucose and insulin metabolism our finding might be connected to the cooccurrence of ADHD and obesity on the one hand and our previous findings on impaired energy impairment in all the investigated PARK2 ADHD CNV cell types(Martins-Silva et al, 2021;Palladino et al, 2020).…”

“…Duplication and deletions were investigated separately as well as grouped and compared to healthy and ADHD wild-type variant carriers. Grouped analysis aimed at increasing sample size, similar to our previous study where similar effects in the same direction have been found in as well deletion as duplication carriers (Palladino et al, 2020). In the following, the terms ADHD PARK2 deletion duplication carriers, wildtype ADHD and wildtype healthy control are used for our cell lines and their donors, adding the respective cell line numbers.…”

“…Furthermore, reduced neuronal process complexity, most likely due to microtubule instability, has been demonstrated in the same model (Ren et al, 2015). In our previous work, we investigated fibroblasts and hiPSC‐derived dopaminergic neurons from ADHD patients carrying PARK2 CNVs and healthy controls (Palladino et al, 2020). Here, we provided preliminary evidence for disturbances in energy metabolism and mitochondrial dysfunction.…”

“…Here, we provided preliminary evidence for disturbances in energy metabolism and mitochondrial dysfunction. Additionally, PARK2 protein expression was reduced in deletion as well as duplication carriers with ADHD, respectively, in comparison to wildtype healthy controls (Palladino et al, 2020).…”

Making Sense of Patient-Derived iPSCs, Transdifferentiated Neurons, Olfactory Neuronal Cells, and Cerebral Organoids as Models for Psychiatric Disorders

“…Palladino et al (2018) investigated a candidate gene for ADHD, PARK2, coding for a protein involved in mitochondria functioning, using human dermal fibroblasts and iPSC-derived dopaminergic neurons from patients suffering from ADHD. They found that carrying a copy number variation of PARK2 might impact mitochondrial dynamics and thereby processes important during developmental periods ( Palladino et al, 2020 ). Considering their results, they suggest substances affecting mitochondria function (antioxidants) as potential treatment options.…”