Genomic, transcriptomic, and metabolomic profiles of hiPSC-derived dopamine neurons from clinically discordant brothers with identical PRKN deletions
Year: 2022
Type: article
Abstract: We previously reported on two brothers who carry identical compound heterozygous PRKN mutations yet present with significantly different Parkinson's Disease (PD) clinical phenotypes. Juvenile cases demonstrate that PD is not necessarily an aging-associated disease. Indeed, evidence for a developmental component to PD pathogenesis is accumulating. Thus, we hypothesized that the presence of additional genetic modifiers, including genetic loci relevant to mesencephalic dopamine neuron development, could potentially contribute to the different clinical manifestations of the two brothers. We differentiated human-induced pluripotent stem cells (hiPSCs) derived from the two brothers into mesencephalic neural precursor cells and early postmitotic dopaminergic neurons and performed wholeexome sequencing and transcriptomic and metabolomic analyses. No significant differences in the expression of canonical dopamine neuron differentiation markers were observed. Yet our transcriptomic analysis revealed a significant downregulation of the expression of three neurodevelopmentally relevant cell adhesion molecules, CNTN6, CNTN4 and CHL1, in the cultures of the more severely affected brother. In addition, several HLA genes, known to play a role in neurodevelopment, were differentially regulated. The expression of EN2, a transcription factor crucial for mesencephalic dopamine neuron development, was also differentially regulated. We further identified differences in cellular processes relevant to dopamine metabolism. Lastly, wholeexome sequencing, transcriptomics and metabolomics data all revealed differences in glutathione (GSH) homeostasis, the dysregulation of which has been previously associated with PD. In summary, we identified genetic differences which could potentially, at least partially, contribute to the discordant clinical PD presentation of the two brothers.
Source: npj Parkinson s Disease
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,190
Funders: U.S. Department of Health and Human Services, Vanderbilt University, Georgia Clinical and Translational Science Alliance, National Institutes of Health, National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences, National Center for Advancing Translational Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G2615776415, Understanding metabolic changes associated with chronic manganese exposure and Alzheimer's Disease, G415212304, Overall: Eunice Kennedy Shriver Intellectual and Developmental Disabilities Research Center at Vanderbilt, G4785944791, G5580019600, G659731888, Integrated ImageXpress Micro Confocal High Content Screening System, Vanderbilt Institute for Clinical and Translational Research (VICTR), Mechanisms of Manganese Neurotoxicity
OpenAlex ID: W4283691982