Dopamine-related oxidative stress and mitochondrial dysfunction in dopaminergic neurons differentiated from deciduous teeth-derived stem cells of children with Down syndrome

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Abstract

Down syndrome (DS) is one of the common genetic disorders caused by the trisomy of human chromosome 21 (HSA21). Mitochondrial dysfunction and redox imbalance play important roles in DS pathology, and altered dopaminergic regulation has been demonstrated in the brain of individuals with DS. However, the pathological association of these elements is not yet fully understood. In this study, we analyzed dopaminergic neurons (DNs) differentiated from deciduous teeth-derived stem cells of children with DS or healthy control children. As previously observed in the analysis of a single case of DS, compared to controls, patient-derived DNs (DS-DNs) displayed shorter neurite outgrowth and fewer branches, as well as downregulated vesicular monoamine transporter 2 and upregulated dopamine transporter 1, both of which are key regulators of dopamine homeostasis in DNs. In agreement with these expression profiles, DS-DNs accumulated dopamine intracellularly and had increased levels of cellular and mitochondrial reactive oxygen species (ROS). DS-DNs showed downregulation of non-canonical Notch ligand, delta-like 1, which may contribute to dopamine accumulation and increased ROS levels through DAT1 upregulation. Furthermore, DS-DNs showed mitochondrial dysfunction in consistent with lower expression of peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) and upregulation of a HSA21-encoded negative regulator of PGC-1α, nuclear receptor-interacting protein 1. These results suggest that dysregulated dopamine homeostasis may participate in oxidative stress and mitochondrial dysfunction of the dopaminergic system in DS.

Original languageEnglish
Pages (from-to)454-467
Number of pages14
JournalFASEB BioAdvances
Volume4
Issue number7
DOIs
Publication statusPublished - Jul 2022

All Science Journal Classification (ASJC) codes

  • Physiology
  • Molecular Medicine
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Cancer Research

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