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Peer-reviewedCC BY 4.0Fluids and Barriers of the CNS

Adult ADHD, PARK2 copy number variations and the blood-brain barrier: Culture duration-dependent metabolic alterations in human induced pluripotent stem cell-derived in vitro models

  • Markus Glaser1
  • Liane Dieterich1
  • Laura Ceslik1
  • Zora Schickardt2,3
  • Sabine Gätzner1
  • Luisa Schmitt1
  • Heike Oberwinkler1
  • Jasmin Reining1
  • Mike Friedrich4
  • Katherina Hemmen4
  • Werner Schmitz5
  • Rhiannon Victoria McNeill2,3
2 more authors
  • Sarah Kittel-Schneider2,3,6
  • Antje Appelt-Menzel1,7
7 affiliations
  1. 1Department for Functional Materials in Medicine and Dentistry, University Hospital Würzburg, Würzburg, Germany
  2. 2Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital Würzburg, Würzburg, Germany
  3. 3Department of Psychiatry and Psychotherapy, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
  4. 4Rudolf Virchow Center for Integrative and Translational Bioimaging, University of Würzburg, Würzburg, Germany
  5. 5Department of Biochemistry and Molecular Biology, University of Würzburg, Würzburg, Germany
  6. 6Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland
  7. 7Translational Center Regenerative Therapies (TLC-RT), Fraunhofer Institute for Silicate Research ISC, Würzburg, Germany
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Abstract

Background: Attention-deficit/hyperactivity disorder (ADHD) is a multifactorial neurodevelopmental disorder in which PARK2 copy number variations (CNVs) constitute a rare genetic risk factor. PARK2 encodes parkin, a key regulator of mitochondrial quality control. Mitochondrial dysfunction is implicated in ADHD pathophysiology and can contribute to blood-brain barrier (BBB) disruption. As BBB disruption remains insufficiently understood in ADHD, this study investigated whether adult ADHD and PARK2 CNVs are accompanied by alterations in BBB phenotype, mitochondrial properties, and cellular metabolism.

Methods: Brain capillary endothelial-like cells (BCECs) were generated using 10 donor-specific human induced pluripotent stem cell (hiPSC) lines from adults with ADHD carrying PARK2 CNVs, alongside PARK2 wild type adults with and without ADHD. BCECs were analyzed at the end of differentiation (day 10) and after prolonged culture (day 17) to assess group-associated phenotypes and culture duration-dependent differences.

Results: Across all groups, BCECs showed brain endothelial marker expression, high transendothelial electrical resistance (TEER), and low sodium fluorescein (NaFl) permeability at day 10. After prolonged culture, NaFl permeability remained low, whereas TEER-based barrier integrity declined. Prolonged culture of BCECs reduced glycolytic ATP production rates while increasing mitochondrial ATP production and its relative contribution to total ATP production, reflecting a metabolic shift from glycolysis toward oxidative phosphorylation. Despite decreased total ATP production after prolonged culture, cellular energy status was largely preserved, alongside overall lower intracellular reactive oxygen species (ROS) and mitochondrial membrane potential. At day 10, BCECs from ADHD donors carrying PARK2 duplications displayed greater mitochondrial abundance, the highest basal and oxidative stress-induced intracellular ROS levels, and reduced TEER-based barrier integrity, while at day 17, BCECs from ADHD donors with PARK2 deletions exhibited the least glycolysis-dependent ATP production profile, although absolute mitochondrial ATP production remained comparable between groups.

Conclusions: Prolonged culture was associated with broad, ADHD- and PARK2 genotype-independent metabolic remodeling, whereas mitochondrial and metabolic alterations associated with ADHD and PARK2 CNVs were overall small. This study identifies culture duration as a critical parameter for the characterization of hiPSC-derived BBB in vitro models and supports the feasibility of using donor-specific BCECs at the end of differentiation to investigate BBB-associated mechanisms in adult ADHD and PARK2 CNVs.

Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12987-026-00892-5.

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Cite

BibTeXRIS
BibTeX
@article{glaser2026adult,
  title = {{Adult ADHD, PARK2 copy number variations and the blood-brain barrier: Culture duration-dependent metabolic alterations in human induced pluripotent stem cell-derived in vitro models}},
  author = {Markus Glaser and Liane Dieterich and Laura Ceslik and Zora Schickardt and Sabine Gätzner and Luisa Schmitt and Heike Oberwinkler and Jasmin Reining and Mike Friedrich and Katherina Hemmen and Werner Schmitz and Rhiannon Victoria McNeill and Sarah Kittel-Schneider and Antje Appelt-Menzel},
  journal = {Fluids and Barriers of the CNS},
  year = {2026},
  month = oct,
  doi = {10.1186/s12987-026-00892-5},
  url = {https://doi.org/10.1186/s12987-026-00892-5},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Adult ADHD, PARK2 copy number variations and the blood-brain barrier: Culture duration-dependent metabolic alterations in human induced pluripotent stem cell-derived in vitro models
AU  - Markus Glaser
AU  - Liane Dieterich
AU  - Laura Ceslik
AU  - Zora Schickardt
AU  - Sabine Gätzner
AU  - Luisa Schmitt
AU  - Heike Oberwinkler
AU  - Jasmin Reining
AU  - Mike Friedrich
AU  - Katherina Hemmen
AU  - Werner Schmitz
AU  - Rhiannon Victoria McNeill
AU  - Sarah Kittel-Schneider
AU  - Antje Appelt-Menzel
PY  - 2026
DA  - 2026/10/24
JO  - Fluids and Barriers of the CNS
DO  - 10.1186/s12987-026-00892-5
UR  - https://doi.org/10.1186/s12987-026-00892-5
AB  - Background: Attention-deficit/hyperactivity disorder (ADHD) is a multifactorial neurodevelopmental disorder in which PARK2 copy number variations (CNVs) constitute a rare genetic risk factor. PARK2 encodes parkin, a key regulator of mitochondrial quality control. Mitochondrial dysfunction is implicated in ADHD pathophysiology and can contribute to blood-brain barrier (BBB) disruption. As BBB disruption remains insufficiently understood in ADHD, this study investigated whether adult ADHD and PARK2 CNVs are accompanied by alterations in BBB phenotype, mitochondrial properties, and cellular metabolism.  Methods: Brain capillary endothelial-like cells (BCECs) were generated using 10 donor-specific human induced pluripotent stem cell (hiPSC) lines from adults with ADHD carrying PARK2 CNVs, alongside PARK2 wild type adults with and without ADHD. BCECs were analyzed at the end of differentiation (day 10) and after prolonged culture (day 17) to assess group-associated phenotypes and culture duration-dependent differences.  Results: Across all groups, BCECs showed brain endothelial marker expression, high transendothelial electrical resistance (TEER), and low sodium fluorescein (NaFl) permeability at day 10. After prolonged culture, NaFl permeability remained low, whereas TEER-based barrier integrity declined. Prolonged culture of BCECs reduced glycolytic ATP production rates while increasing mitochondrial ATP production and its relative contribution to total ATP production, reflecting a metabolic shift from glycolysis toward oxidative phosphorylation. Despite decreased total ATP production after prolonged culture, cellular energy status was largely preserved, alongside overall lower intracellular reactive oxygen species (ROS) and mitochondrial membrane potential. At day 10, BCECs from ADHD donors carrying PARK2 duplications displayed greater mitochondrial abundance, the highest basal and oxidative stress-induced intracellular ROS levels, and reduced TEER-based barrier integrity, while at day 17, BCECs from ADHD donors with PARK2 deletions exhibited the least glycolysis-dependent ATP production profile, although absolute mitochondrial ATP production remained comparable between groups.  Conclusions: Prolonged culture was associated with broad, ADHD- and PARK2 genotype-independent metabolic remodeling, whereas mitochondrial and metabolic alterations associated with ADHD and PARK2 CNVs were overall small. This study identifies culture duration as a critical parameter for the characterization of hiPSC-derived BBB in vitro models and supports the feasibility of using donor-specific BCECs at the end of differentiation to investigate BBB-associated mechanisms in adult ADHD and PARK2 CNVs.  Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12987-026-00892-5.
SN  - 2045-8118
ER  -