H50Q mutation in alpha-Synuclein impairs the insulin signaling pathway and induces neuroinflammation in the Drosophila model

Abstract

H50Q mutations in the SNCA gene, also known as also known as the alpha-Synuclein (α-Syn), have been causally linked to familial Parkinson's disease (PD). PD is primarily characterized by the progressive loss of dopaminergic neurons in the substantia nigra region of the brain.α-Syn- plays a pivotal role in the formation of Lewy bodies (LB), a prominent pathological marker in PD. Growing evidence has highlighted the involvement of the insulin signaling pathway dysfunction in various neurodegenerative models. This study aimed to explore how the H50Q mutation in α-Syn influences the insulin signaling pathway and the overall lifespan of fruit flies afflicted with PD. It has been established that a mutation in α-Syn affects mitochondrial function and increases oxidative stress, ultimately contributing to the death of dopaminergic neurons. The impairment of mitochondrial function disrupts metabolism and exerts an adverse effect on the insulin signaling pathway. Furthermore, the unfolded protein response of the endoplasmic reticulum (ER) are investigated and observed a decrease in the expression of PERK (Protein kinase R-like ER kinase) during ER stress. These findings confirm the intricate interplay between the insulin signaling pathway and the activation of the PERK-ER stress pathway. However, the degeneration of neurons triggers a neuroinflammatory response, which are found to be mitigated by the improvement of insulin signaling and the PERK-ER stress-related pathway. The results of this studyshed light on the novel regulatory role of PERK within the insulin signaling pathway and suggest its potential as a therapeutic candidate for modulating neuroinflammation in the context of α-Syn -associated PD pathology.