A reversible state of hypometabolism in a human cellular model of sporadic Parkinson’s disease
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order caused by multiple genetic and environmental factors. Mitochondrial
dysfunction is one contributing factor, but its role at different stages of disease
progression is not fully understood. Here, we showed that neural precursor
cells and dopaminergic neurons derived from induced pluripotent stem cells
(hiPSCs) from sPD patients exhibited a hypometabolism. Further analysis
based on transcriptomics, proteomics, and metabolomics identified the citric
acid cycle, specifically the α-ketoglutarate dehydrogenase complex (OGDHC),
as bottleneck in sPD metabolism. A follow-up study of the patients approxi-
mately 10 years after initial biopsy demonstrated a correlation between
OGDHC activity in our cellular model and the disease progression. In addition,
the alterations in cellular metabolism observed in our cellular model were
restored by interfering with the enhanced SHH signal transduction in sPD.
Thus, inhibiting overactive SHH signaling may have potential as neuropro-
tective therapy during early stages of sPD.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 7674 |
| Tidsskrift | Nature Communications |
| Vol/bind | 14 |
| Udgave nummer | 1 |
| Antal sider | 24 |
| ISSN | 2041-1723 |
| DOI | |
| Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
We thank Franz Marxreiter (University Erlangen) for providing baseline clinical information; Annerose Kurz-Drexler, Tanja Orschmann, Susanne Badeke, Esther Álvarez Sánchez, Jessica Häußler, and Laura Snaidr for excellent technical assistance; Alessandra Moretti (TUM), Antje Gertes (HZM), Günter Höglinger (LMU), and Heiko Lickert (HZM) for discussions and comments. This work was supported in part by the Bavarian Ministry of Science and the Arts in the framework of the ForIPS consortium (C.S., W.W., J.W., and B.W.), the ForInter consortium (B.W., J.W., and F.J.T.), by the German Federal Ministry of Education and Research (BMBF) through ACS_iIMMUNE (no. 01EO2105 to M.R.) and the Integrated Network MitoPD (Mitochondrial endophenotypes of Morbus Parkinson), under the auspices of the e:Med Programme (grant 031A430E to W.W.), through the Joint Project HIT-Tau (High Throughput Approaches for the Individualized Therapy of Tau-Related Diseases—TP2: Grant 01EK1605C (to W.W. and D.T.), by the AMPro project “Aging and Metabolic Programming”, as well as by “ExNet-0041-Phase2-3 (SyNergy-HZM)” through the Initiative and Network Fund of the Helmholtz Association (to F.G. and W.W.), through the Niedersächsisches Vorab (grant VWZN3266 to K.H.), through the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) project HI1400/3-1 (K.H.), CRU5024 WI 3567/4-1 (B.W.) and WI 1620/4-1 (J.W.). Open Access funding enabled and organized by Projekt DEAL.
Funding Information:
We thank Franz Marxreiter (University Erlangen) for providing baseline clinical information; Annerose Kurz-Drexler, Tanja Orschmann, Susanne Badeke, Esther Álvarez Sánchez, Jessica Häußler, and Laura Snaidr for excellent technical assistance; Alessandra Moretti (TUM), Antje Gertes (HZM), Günter Höglinger (LMU), and Heiko Lickert (HZM) for discussions and comments. This work was supported in part by the Bavarian Ministry of Science and the Arts in the framework of the ForIPS consortium (C.S., W.W., J.W., and B.W.), the ForInter consortium (B.W., J.W., and F.J.T.), by the German Federal Ministry of Education and Research (BMBF) through ACS_iIMMUNE (no. 01EO2105 to M.R.) and the Integrated Network MitoPD (Mitochondrial endophenotypes of Morbus Parkinson), under the auspices of the e:Med Programme (grant 031A430E to W.W.), through the Joint Project HIT-Tau (High Throughput Approaches for the Individualized Therapy of Tau-Related Diseases—TP2: Grant 01EK1605C (to W.W. and D.T.), by the AMPro project “Aging and Metabolic Programming”, as well as by “ExNet-0041-Phase2-3 (SyNergy-HZM)” through the Initiative and Network Fund of the Helmholtz Association (to F.G. and W.W.), through the Niedersächsisches Vorab (grant VWZN3266 to K.H.), through the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) project HI1400/3-1 (K.H.), CRU5024 WI 3567/4-1 (B.W.) and WI 1620/4-1 (J.W.). Open Access funding enabled and organized by Projekt DEAL.
Publisher Copyright:
© 2023, The Author(s).
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