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Genomic, transcriptomic, and metabolomic profiles of hiPSC-derived dopamine neurons from clinically discordant brothers with identical PRKN deletions.

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.

SUBMITTER: Cukier HN

PROVIDER: S-EPMC9243035 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Genomic, transcriptomic, and metabolomic profiles of hiPSC-derived dopamine neurons from clinically discordant brothers with identical PRKN deletions.

Cukier Holly N HN Kim Hyunjin H Griswold Anthony J AJ Codreanu Simona G SG Prince Lisa M LM Sherrod Stacy D SD McLean John A JA Dykxhoorn Derek M DM Ess Kevin C KC Hedera Peter P Bowman Aaron B AB Neely M Diana MD

NPJ Parkinson's disease 20220629 1

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, ...[more]

PMID: 35768426

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Project description:We have previously reported on two brothers, PM and SM, that carry identical compound heterozygous PRKN mutations but show significantly different clinical Parkinson disease (PD) phenotypes. The occurrence of juvenile cases demonstrates that PD is not necessarily an age-associated disease; indeed, evidence is accumulating that there is a developmental component to PD pathogenesis. The divergence in the clinical presentations between PM and SM lead us to hypothesize that an additional genetic modifier(s) may influence the risk conferred by PRKN. To test our hypothesis, we differentiated human induced pluripotent stem cells (iPSCs) from SM and PM into mitotically active mesencephalic neural precursor cells (floor plate cells) and early postmitotic dopaminergic neurons, and performed whole exome sequencing, and transcriptomic and metabolomics analysis. Our transcriptomic analysis revealed a significant down regulation of three known neurodevelopmentally relevant cell adhesion molecules in PM compared to SM cultures on days 11 and 25 of differentiation, CNTN4, CNTN6, and CHL1. In addition, several HLA genes, known to play a role in neurodevelopment, independent of their well-established function in immunity, were differentially regulated in developing dopamine neurons. EN2, a transcription factor crucial for mesencephalic dopamine neuron development, was also differentially regulated. We further report on a single nucleotide polymorphism in DBH, a gene encoding an enzyme involved in dopamine metabolism, as well as differential expression. Our metabolomics data reveal differential biosynthesis of tyrosine, the precursor for dopamine synthesis. Lastly, our whole exome sequencing revealed the homozygous deletion in SM of two glutathione S-transferases, GSTM1 and GSTT1, which encode enzymes involved in glutathione (GSH) metabolism. Moreover, our RNA sequencing analysis shows a lack of expression of these two enzymes in SM cells and our metabolomics analysis indicates differences in GSH homeostasis between SM and PM neurons. This finding builds on previous evidence of glutathione dysregulation being implicated in PD pathogenesis. Our data support our hypothesis that additional genetic differences at least partially underlie the differential clinical PD presentation between PM and SM.

Dataset Information

Genomic, transcriptomic, and metabolomic profiles of hiPSC-derived dopamine neurons from clinically discordant brothers with identical PRKN deletions.

Publications

Genomic, transcriptomic, and metabolomic profiles of hiPSC-derived dopamine neurons from clinically discordant brothers with identical PRKN deletions.

Similar Datasets

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