[en] 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.
Disciplines :
Life sciences: Multidisciplinary, general & others
Author, co-author :
ZAGARE, Alise ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Developmental and Cellular Biology > Team Jens Christian SCHWAMBORN
Kurlovics, Janis; Bioinformatics Lab, Rīga Stradiņš University, Riga, Latvia
ALMEIDA, Catarina ; University of Luxembourg ; Health Sciences Research Center, Faculty of Health Sciences Research, Faculty of Health Sciences, University of Beira Interior, Covilhã, Portugal
FERRANTE, Daniele ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Translational Neuroscience > Team Rejko KRÜGER
FRANGENBERG-HOFF, Daniela ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Developmental and Cellular Biology
VITALI, Armelle ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Translational Neuroscience > Team Rejko KRÜGER
GOMEZ GIRO, Gemma ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Developmental and Cellular Biology > Team Jens Christian SCHWAMBORN
JÄGER, Christian ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Scientific Central Services > Metabolomics Platform
ANTONY, Paul ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Scientific Central Services > Imaging Platform
HALDER, Rashi ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Scientific Central Services > Sequencing Platform
KRÜGER, Rejko ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience ; Transversal Translational Medicine, Luxembourg Institute of Health (LIH), Strassen, Luxembourg
GLAAB, Enrico ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Biomedical Data Science
Stalidzans, Egils; Bioinformatics Lab, Rīga Stradiņš University, Riga, Latvia
ARENA, Giuseppe ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Translational Neuroscience > Team Rejko KRÜGER
SCHWAMBORN, Jens Christian ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Developmental and Cellular Biology
FNR15850547 - PINK1-DiaPDs - Pink1-related Molecular Mechanisms To Dissect The Connection Between Type 2 Diabetes And Insulin Resistance In Parkinson’S Disease, 2021 (01/01/2022-31/08/2024) - Giuseppe Arena FNR11264123 - NCER-PD - Ncer-pd, 2015 (01/06/2015-31/05/2023) - Rejko Krüger
Funders :
Fonds National de la Recherche Luxembourg Fonds National de la Recherche Luxembourg
Funding text :
This research was funded by the FNR-Luxembourg. For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript (AAM) version arising from this submission.We would like to thank Prof. Dr. Rudi Balling for the valuable ideas that inspired this project. We acknowledge the support of the LCSB Bio-imaging Platform for high-content imaging and image analysis script optimisation, and assistance with flow cytometry experiments. RNA sequencing for RNA integration into metabolic models was performed at the LCSB Sequencing Platform. We would also like to extend our thanks to the metabolomics platforms at the LIH (particularly Laura Neises and Johannes Meiser) and the LCSB for conducting the metabolomics experiments, as well as the KU Leuven technology platform \u2013 Lipometrix for performing the lipidomics analysis. The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was mainly supported by the internal flagship project at the Luxembourg Centre for Systems Biomedicine and by the Luxembourg National Research Fund CORE grant to GA (C21/BM/15850547/PINK1-DiaPDs). Further, we acknowledge support from the National Centre of Excellence in Research on Parkinson\u2019s Disease (NCER-PD) which is funded by the Luxembourg National Research Fund (FNR/NCER13/BM/11264123).The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was mainly supported by the internal flagship project at the Luxembourg Centre for Systems Biomedicine and by the Luxembourg National Research Fund CORE grant to GA (C21/BM/15850547/PINK1-DiaPDs). Further, we acknowledge support from the National Centre of Excellence in Research on Parkinson\u2019s Disease (NCER-PD) which is funded by the Luxembourg National Research Fund (FNR/NCER13/BM/11264123).
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