Insulin Resistance Is a Modifying Factor for Parkinson's Disease

Abstract 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. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.