Insulin resistance is a modifying factor for Parkinson’s disease#

Authors#

Alise Zagare, Ahmed Hemedan, Catarina Almeida, Daniela Frangenberg, Gemma Gomez Giro, Paul Antony, Rashi Halder, Rejko Krüger, Enrico Glaab, Marek Ostaszewski, Giuseppe Arena, Jens Christian Schwamborn

Abstract#

Background Parkinson’s disease (PD) is the second most common, and the fastest-growing neurodegenerative disorder with unclear aetiology 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 GBA mutation-associated Parkinson’s disease pathogenesis and phenotype severity.

Methods Midbrain organoids, generated from iPSCs of PD patients carrying the GBA-N307S heterozygous mutation (GBA-PD) and healthy donors, were exposed to different insulin concentrations to modify insulin signalling function. Transcriptomics analysis was performed to explore insulin signalling gene expression patterns in GBA-PD and to find a potential target for GBA-PD-associated phenotype rescue.

Results The insulin signalling pathway genes show dysregulation in GBA-PD. Particularly, we highlight that a knock-down 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 signalling dysfunction plays a substantial role in GBA-PD pathogenesis, exacerbating dopaminergic neuron death.