Summary of Study ST002389

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 PR001536. The data can be accessed directly via it's Project DOI: 10.21228/M8512J This work is supported by NIH grant, U2C- DK119886.

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This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.

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Study IDST002389
Study TitleAlterations in SHH signal transduction introduce a state of hypometabolism in sporadic Parkinson's disease
Study SummaryInduced pluripotent stem cells (iPSC) derived from sporadic Parkinson's disease patients and healthy control subjects were used for disease modeling. iPSC were differentiated towards midbrain dopaminergic neurons. For metabolic analysis, midbrain neuronal precursor cells were cultivated in growth medium supplemented with either 1.25 mM [U-13C]-glutamine or 21.25 mM [U-13C]-glucose. Metabolites were extracted and analyzed using GC-MS. The MetaboliteDetector software was used to analyze chromatograms, calculate mass isotopomer distributions (MIDs) and perform relative comparison of metabolite levels.
Institute
Helmholtz Centre for Environmental Research
DepartmentInstitute of Developmental Genetics
Last NameSchmidt
First NameSebastian
AddressIngolstädter Landstraße 1, 85764 Munich, Germany
Emailsebastian.schmidt@helmholtz-muenchen.de
Phone+4989318743660
Submit Date2022-12-03
Num Groups3
Total Subjects13
Raw Data AvailableYes
Raw Data File Type(s)bin
Analysis Type DetailGC-MS
Release Date2023-10-06
Release Version1
Sebastian Schmidt Sebastian Schmidt
https://dx.doi.org/10.21228/M8512J
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

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Project:

Project ID:PR001536
Project DOI:doi: 10.21228/M8512J
Project Title:Alterations in SHH signal transduction introduce a state of hypometabolism in sporadic Parkinson's disease
Project Type:Isotopic labeling
Project Summary:Sporadic Parkinson’s Disease (sPD) is a progressive neurodegenerative disorder caused by multiple genetic and environmental factors with largely unknown etiology. Prominent pathological culprits include metabolic as well as mitochondrial alterations which have been identified in patients, however, their relevance at different stages of disease progression or their connection remains largely elusive. Here, human iPSCs from late-onset sPD patients were used for disease modeling. Following long-term in vitro cultivation, exclusively neural cells derived from sPD patients developed reduced mitochondrial respiration and glucose consumption reflecting an sPD-specific state of hypometabolism. A multilayered omics analysis based on transcriptomics, proteomics, and metabolomics allowed us to identify the citric acid cycle as being the bottleneck in sPD metabolism. A 13C metabolic flux analysis further unraveled the a-ketoglutarate dehydrogenase complex as being central for a reduced flux through the citric acid cycle. This resulted in a substrate availability problem for the electron transport chain and thus reduced mitochondrial oxygen consumption and ATP production. Notably, these alterations in cellular metabolism were evoked by altered SHH signal transduction due to dysfunctional primary cilia. Upon inhibiting the enhanced SHH signal transduction in sPD, glucose uptake and the activity of the a-ketoglutarate dehydrogenase complex could be restored. Thus, inhibiting overactive SHH signaling may be a potential neuroprotective therapy during the early stages of sPD.
Institute:Helmholtz Centre for Environmental Research
Department:Institute of Developmental Genetics
Last Name:Schmidt
First Name:Sebastian
Address:Ingolstädter Landstraße 1, 85764 Munich, Germany
Email:sebastian.schmidt@helmholtz-muenchen.de
Phone:+4989318743660
Contributors:Karsten Hiller, Alexander Heinz
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