[en] [en] BACKGROUND: Parkinson's disease (PD) is the second most common, and the fastest-growing neurodegenerative disorder with unclear etiology in most cases. Therefore, the identification of non-genetic risk factors for PD pathology is crucial to develop effective preventative or therapeutic strategies. An increasing number of evidence suggests that central insulin resistance might have an essential role in PD pathology. Nevertheless, it is not clear whether insulin resistance arises from external factors/lifestyle, comorbidities such as type 2 diabetes or it can occur in a PD patient's brain independently from peripheral insulin resistance.
OBJECTIVE: We aimed to investigate insulin resistance and its role in GBA1 mutation-associated PD pathogenesis and phenotype severity.
METHODS: Midbrain organoids, generated from induced pluripotent stem cells (iPSCs) of PD patients carrying the GBA1-N370S heterozygous mutation (GBA-PD) and healthy donors, were exposed to different insulin concentrations to modify insulin signaling function. Transcriptomics analysis was performed to explore insulin signaling gene expression patterns in GBA-PD and to find a potential target for GBA-PD-associated phenotype rescue.
RESULTS: The insulin signaling pathway genes show dysregulation in GBA-PD. Particularly, we highlight that a knockdown of FOXO1 mitigates the loss of dopaminergic neurons and cellular death in GBA-PD. Additionally, our findings suggest a promising therapeutic potential of the anti-diabetic drug Pioglitazone in decreasing dopaminergic neuron loss associated with GBA-PD.
CONCLUSION: Local insulin signaling dysfunction plays a substantial role in GBA-PD pathogenesis, exacerbating dopaminergic neuron death.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
ZAGARE, Alise ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Developmental and Cellular Biology
HEMEDAN, Ahmed ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core
ALMEIDA, Catarina ; University of Luxembourg ; Health Sciences Research Center, Faculty of Health Sciences Research, Faculty of Health Sciences, University of Beira Interior, Covilhã, Portugal
Frangenberg, Daniela; Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg
Gomez-Giro, Gemma; Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg
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; Translational Neuroscience, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg ; Transversal Translational Medicine, Luxembourg Institute of Health (LIH), Strassen, Luxembourg
OSTASZEWSKI, Marek ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core
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
External co-authors :
yes
Language :
English
Title :
Insulin Resistance Is a Modifying Factor for Parkinson's Disease.
Publication date :
05 November 2024
Journal title :
Movement Disorders
ISSN :
0885-3185
eISSN :
1531-8257
Publisher :
John Wiley and Sons Inc, United States
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
Fonds National de la Recherche Luxembourg
Funding text :
: 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\u2010DiaPDs). Further, we acknowledge support from the National Centre of Excellence in Research on Parkinson's Disease (NCER\u2010PD), which is funded by the Luxembourg National Research Fund (FNR/NCER13/BM/11264123). Funding agencies
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