Insulin resistance compromises midbrain organoid neuronal activity and metabolic efficiency predisposing to Parkinson’s disease pathology
Growing evidence indicates that type 2 diabetes (T2D) is associated with an increased risk of developing Parkinson’s disease (PD) through shared disease mechanisms. Studies show that insulin resistance, which is the driving pathophysiological mechanism of T2D plays a major role in neurodegeneration...
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| Format: | Article |
| Language: | English |
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SAGE Publishing
2025-01-01
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| Series: | Journal of Tissue Engineering |
| Online Access: | https://doi.org/10.1177/20417314241295928 |
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| author | Alise Zagare Janis Kurlovics Catarina Almeida Daniele Ferrante Daniela Frangenberg Armelle Vitali Gemma Gomez-Giro Christian Jäger Paul Antony Rashi Halder Rejko Krüger Enrico Glaab Egils Stalidzans Giuseppe Arena Jens C Schwamborn |
| author_facet | Alise Zagare Janis Kurlovics Catarina Almeida Daniele Ferrante Daniela Frangenberg Armelle Vitali Gemma Gomez-Giro Christian Jäger Paul Antony Rashi Halder Rejko Krüger Enrico Glaab Egils Stalidzans Giuseppe Arena Jens C Schwamborn |
| author_sort | Alise Zagare |
| collection | DOAJ |
| description | Growing evidence indicates that type 2 diabetes (T2D) is associated with an increased risk of developing Parkinson’s disease (PD) through shared disease mechanisms. Studies show that insulin resistance, which is the driving pathophysiological mechanism of T2D plays a major role in neurodegeneration by impairing neuronal functionality, metabolism and survival. To investigate insulin resistance caused pathological changes in the human midbrain, which could predispose a healthy midbrain to PD development, we exposed iPSC-derived human midbrain organoids from healthy individuals to either high insulin concentration, promoting insulin resistance, or to more physiological insulin concentration restoring insulin signalling function. We combined experimental methods with metabolic modelling to identify the most insulin resistance-dependent pathogenic processes. We demonstrate that insulin resistance compromises organoid metabolic efficiency, leading to increased levels of oxidative stress. Additionally, insulin-resistant midbrain organoids showed decreased neuronal activity and reduced amount of dopaminergic neurons, highlighting insulin resistance as a significant target in PD prevention. |
| format | Article |
| id | doaj-art-b8355bfa775648248085ab372f045d41 |
| institution | Kabale University |
| issn | 2041-7314 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | SAGE Publishing |
| record_format | Article |
| series | Journal of Tissue Engineering |
| spelling | doaj-art-b8355bfa775648248085ab372f045d412025-01-29T09:03:33ZengSAGE PublishingJournal of Tissue Engineering2041-73142025-01-011610.1177/20417314241295928Insulin resistance compromises midbrain organoid neuronal activity and metabolic efficiency predisposing to Parkinson’s disease pathologyAlise Zagare0Janis Kurlovics1Catarina Almeida2Daniele Ferrante3Daniela Frangenberg4Armelle Vitali5Gemma Gomez-Giro6Christian Jäger7Paul Antony8Rashi Halder9Rejko Krüger10Enrico Glaab11Egils Stalidzans12Giuseppe Arena13Jens C Schwamborn14Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, LuxembourgBioinformatics Lab, Rīga Stradiņš University, Riga, LatviaHealth Sciences Research Center, Faculty of Health Sciences Research, Faculty of Health Sciences, University of Beira Interior, Covilhã, PortugalDevelopmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, LuxembourgDevelopmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, LuxembourgTranslational Neuroscience, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, LuxembourgDevelopmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, LuxembourgMetabolomics Platform, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, LuxembourgBioimaging Platform, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, LuxembourgSequencing Platform, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, LuxembourgTransversal Translational Medicine, Luxembourg Institute of Health (LIH), Strassen, LuxembourgBiomedical Data Science, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, LuxembourgBioinformatics Lab, Rīga Stradiņš University, Riga, LatviaTranslational Neuroscience, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, LuxembourgDevelopmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, LuxembourgGrowing evidence indicates that type 2 diabetes (T2D) is associated with an increased risk of developing Parkinson’s disease (PD) through shared disease mechanisms. Studies show that insulin resistance, which is the driving pathophysiological mechanism of T2D plays a major role in neurodegeneration by impairing neuronal functionality, metabolism and survival. To investigate insulin resistance caused pathological changes in the human midbrain, which could predispose a healthy midbrain to PD development, we exposed iPSC-derived human midbrain organoids from healthy individuals to either high insulin concentration, promoting insulin resistance, or to more physiological insulin concentration restoring insulin signalling function. We combined experimental methods with metabolic modelling to identify the most insulin resistance-dependent pathogenic processes. We demonstrate that insulin resistance compromises organoid metabolic efficiency, leading to increased levels of oxidative stress. Additionally, insulin-resistant midbrain organoids showed decreased neuronal activity and reduced amount of dopaminergic neurons, highlighting insulin resistance as a significant target in PD prevention.https://doi.org/10.1177/20417314241295928 |
| spellingShingle | Alise Zagare Janis Kurlovics Catarina Almeida Daniele Ferrante Daniela Frangenberg Armelle Vitali Gemma Gomez-Giro Christian Jäger Paul Antony Rashi Halder Rejko Krüger Enrico Glaab Egils Stalidzans Giuseppe Arena Jens C Schwamborn Insulin resistance compromises midbrain organoid neuronal activity and metabolic efficiency predisposing to Parkinson’s disease pathology Journal of Tissue Engineering |
| title | Insulin resistance compromises midbrain organoid neuronal activity and metabolic efficiency predisposing to Parkinson’s disease pathology |
| title_full | Insulin resistance compromises midbrain organoid neuronal activity and metabolic efficiency predisposing to Parkinson’s disease pathology |
| title_fullStr | Insulin resistance compromises midbrain organoid neuronal activity and metabolic efficiency predisposing to Parkinson’s disease pathology |
| title_full_unstemmed | Insulin resistance compromises midbrain organoid neuronal activity and metabolic efficiency predisposing to Parkinson’s disease pathology |
| title_short | Insulin resistance compromises midbrain organoid neuronal activity and metabolic efficiency predisposing to Parkinson’s disease pathology |
| title_sort | insulin resistance compromises midbrain organoid neuronal activity and metabolic efficiency predisposing to parkinson s disease pathology |
| url | https://doi.org/10.1177/20417314241295928 |
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