Summary of project PR001244
This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR001244. The data can be accessed directly via it's Project DOI: 10.21228/M8X40N This work is supported by NIH grant, U2C- DK119886.
See: https://www.metabolomicsworkbench.org/about/howtocite.php
| Project ID: | PR001244 |
| Project DOI: | doi: 10.21228/M8X40N |
| Project Title: | Untargeted Mass Spectrometry Metabolomic Profiles of iPSC-derived Dopaminergic Neurons from Clinically Discordant Brothers with Identical PRKN Deletions |
| Project Type: | Untargeted Metabolomics analysis |
| Project Summary: | We have previously reported on two brothers, PM and SM, who carry identical compound heterozygous PRKN mutations but present with very different clinical Parkinson’s disease (PD) phenotypes, with PM, but not SM having been diagnosed with early onset disease. 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. We hypothesize that additional genetic modifiers, potentially including genetic loci relevant to mesencephalic dopamine neuron development may play a role. We differentiated human-induced pluripotent stem cells (hiPSCs) derived from SM and PM into mitotically active mesencephalic neural precursor cells and early post mitotic dopaminergic neurons and performed whole exome sequencing, transcriptomic- and metabolomic analyses. No significant differences in canonical markers of differentiation were observed between SM and PM. Yet our transcriptomic analysis revealed a significant down regulation of three neurodevelopmentally relevant cell adhesion molecules, CNTN6, CNTN4 and CHL1 in PM - compared to SM cultures on days 11 and 25 of differentiation. In addition, several HLA genes, known to play a role in neurodevelopment, independent of their well-established function in immunity, were differentially regulated in PM and SM developing dopamine neurons. EN2, a transcription factor crucial for mesencephalic dopamine neuron development, was also differentially regulated. We further observed differences in cellular processes relevant to dopamine homeostasis. Lastly, our whole exome sequencing, transcriptomics and metabolomics data of SM and PM neurons revealed differences in GSH homeostasis, the dysregulation of which has been associated with PD. |
| Institute: | VANDERBILT UNIVERSITY |
| Department: | Chemistry |
| Laboratory: | Center for Innovative Technology |
| Last Name: | CODREANU |
| First Name: | SIMONA |
| Address: | 1234 STEVENSON CENTER LANE, NASHVILLE, TN, 37235, USA |
| Email: | SIMONA.CODREANU@VANDERBILT.EDU |
| Phone: | 6158758422 |
Summary of all studies in project PR001244
| Study ID | Study Title | Species | Institute | Analysis(* : Contains Untargted data) | Release Date | Version | Samples | Download(* : Contains raw data) |
|---|---|---|---|---|---|---|---|---|
| ST001957 | Untargeted Mass Spectrometry Metabolomic Profiles of iPSC-derived Dopaminergic Neurons from Clinically Discordant Brothers with Identical PRKN Deletions | Homo sapiens | Vanderbilt University | MS* | 2022-01-17 | 1 | 207 | Uploaded data (45.3G)* |
