A reversible state of hypometabolism in a human cellular model of sporadic Parkinson’s disease
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A reversible state of hypometabolism in a human cellular model of sporadic Parkinson’s disease. / Schmidt, Sebastian; Stautner, Constantin; Vu, Duc Tung; Heinz, Alexander; Regensburger, Martin; Karayel, Ozge; Trümbach, Dietrich; Artati, Anna; Kaltenhäuser, Sabine; Nassef, Mohamed Zakaria; Hembach, Sina; Steinert, Letyfee; Winner, Beate; Jürgen, Winkler; Jastroch, Martin; Luecken, Malte D.; Theis, Fabian J.; Westmeyer, Gil Gregor; Adamski, Jerzy; Mann, Matthias; Hiller, Karsten; Giesert, Florian; Vogt Weisenhorn, Daniela M.; Wurst, Wolfgang.
In: Nature Communications, Vol. 14, No. 1, 7674, 2023.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - A reversible state of hypometabolism in a human cellular model of sporadic Parkinson’s disease
AU - Schmidt, Sebastian
AU - Stautner, Constantin
AU - Vu, Duc Tung
AU - Heinz, Alexander
AU - Regensburger, Martin
AU - Karayel, Ozge
AU - Trümbach, Dietrich
AU - Artati, Anna
AU - Kaltenhäuser, Sabine
AU - Nassef, Mohamed Zakaria
AU - Hembach, Sina
AU - Steinert, Letyfee
AU - Winner, Beate
AU - Jürgen, Winkler
AU - Jastroch, Martin
AU - Luecken, Malte D.
AU - Theis, Fabian J.
AU - Westmeyer, Gil Gregor
AU - Adamski, Jerzy
AU - Mann, Matthias
AU - Hiller, Karsten
AU - Giesert, Florian
AU - Vogt Weisenhorn, Daniela M.
AU - Wurst, Wolfgang
N1 - Publisher Copyright: © 2023, The Author(s).
PY - 2023
Y1 - 2023
N2 - Sporadic Parkinson’s Disease (sPD) is a progressive neurodegenerative disorder 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 approximately 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 neuroprotective therapy during early stages of sPD.
AB - Sporadic Parkinson’s Disease (sPD) is a progressive neurodegenerative disorder 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 approximately 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 neuroprotective therapy during early stages of sPD.
U2 - 10.1038/s41467-023-42862-7
DO - 10.1038/s41467-023-42862-7
M3 - Journal article
C2 - 37996418
AN - SCOPUS:85177734756
VL - 14
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 7674
ER -
ID: 379170349