Mutation in α-Syn impairs insulin signaling pathway and induces neuroinflammation in the α-Syn Parkinson's Drosophila model.

Abstract

Mutations in the alpha-synuclein (α-Syn) gene 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), serving as a prominent pathological marker in PD. Growing evidence has illuminated the involvement of the insulin signaling pathway dysfunction in various neurodegenerative models. This study set out to explore how α-Syn influences the insulin signaling pathway and the overall lifespan of fruit flies afflicted with Parkinson's disease. It has been established that the α-Syn gene affects mitochondrial function, with mutations leading to mitochondrial impairments and increased oxidative stress, which ultimately contributes to the death of dopaminergic neurons.The impairment of mitochondrial function disrupts metabolism and exerts an adverse influence 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 confirmed 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. This study's results shed 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 Parkinson's Disease pathology.