دورية أكاديمية
أعرض في EDS

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

التفاصيل البيبلوغرافية
العنوان: Genomic, transcriptomic, and metabolomic profiles of hiPSC-derived dopamine neurons from clinically discordant brothers with identical PRKN deletions.
المؤلفون: Cukier HN; John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.; Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA.; John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA., Kim H; School of Health Sciences, Purdue University, West Lafayette, Indiana, IN, USA., Griswold AJ; John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.; John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA., Codreanu SG; Center for Innovative Technology, Vanderbilt University, Nashville, TN, USA.; Department of Chemistry, Vanderbilt University, Nashville, TN, USA., Prince LM; School of Health Sciences, Purdue University, West Lafayette, Indiana, IN, USA., Sherrod SD; Center for Innovative Technology, Vanderbilt University, Nashville, TN, USA.; Department of Chemistry, Vanderbilt University, Nashville, TN, USA., McLean JA; Center for Innovative Technology, Vanderbilt University, Nashville, TN, USA.; Department of Chemistry, Vanderbilt University, Nashville, TN, USA., Dykxhoorn DM; John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.; John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA., Ess KC; Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA.; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA., Hedera P; Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA.; Department of Neurology, University of Louisville, Louisville, KY, USA., Bowman AB; School of Health Sciences, Purdue University, West Lafayette, Indiana, IN, USA. bowma117@purdue.edu., Neely MD; Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA. diana.neely@vumc.org.; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA. diana.neely@vumc.org.
المصدر: NPJ Parkinson's disease [NPJ Parkinsons Dis] 2022 Jun 29; Vol. 8 (1), pp. 84. Date of Electronic Publication: 2022 Jun 29.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Nature Publishing Group Country of Publication: United States NLM ID: 101675390 Publication Model: Electronic Cited Medium: Print ISSN: 2373-8057 (Print) Linking ISSN: 23738057 NLM ISO Abbreviation: NPJ Parkinsons Dis Subsets: PubMed not MEDLINE
أسماء مطبوعة: Original Publication: [New York, NY] : Nature Publishing Group : Parkinson's Disease Foundation, [2015]-
مستخلص: 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.
(© 2022. The Author(s).)
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معلومات مُعتمدة: S10 OD028719 United States OD NIH HHS; R03 NS125243 United States NS NINDS NIH HHS; P50 HD103537 United States HD NICHD NIH HHS; UL1 TR002243 United States TR NCATS NIH HHS; R01 ES010563 United States ES NIEHS NIH HHS
تواريخ الأحداث: Date Created: 20220629 Latest Revision: 20240517
رمز التحديث: 20240517
مُعرف محوري في PubMed: PMC9243035
DOI: 10.1038/s41531-022-00346-3
PMID: 35768426
قاعدة البيانات: MEDLINE
الوصف
تدمد:2373-8057
DOI:10.1038/s41531-022-00346-3