Intestine-derived α-synuclein initiates and aggravates pathogenesis of Parkinson’s disease in Drosophila

Abstract Background Synucleinopathies, the aberrant aggregation of α-Synuclein (α-Syn), are key pathological features of Parkinson’s disease (PD), but the precise role of intestinal α-Syn in the progression of PD remains largely elusive. In a number of genetic PD Drosophila models, α-Syn is frequently ectopically expressed in the neural system to investigate the pathobiology of PD. Method Life span, survival, immunofluorescence and climbing were carried out to evaluate the progress of intestinal PD flies, in which human α-Syn was overexpressed in Drosophila guts. Immunofluorescence, Western blotting and ROS staining were employed to assess the effects of intestinal α-Syn on intestinal dysplasia. High-throughput RNA and 16S rRNA gene sequencing, quantitative RT‐PCR, immunofluorescence, and ROS staining were performed to determine the molecular mechanism of the PD pathogenesis. Results Here, we investigate the potential role of intestinal α-Syn in PD pathogenesis using a Drosophila model. We found that intestinal α-Syn alone recapitulates many features of PD-associated synucleinopathies, including impaired life span, loss of dopaminergic neurons, and progressive motor defects. Intestine-derived α-Syn disrupts intestinal homeostasis and accelerates the onset of intestinal ageing. Moreover, intestinal expression of α-Syn induces dysbiosis, while microbiome depletion is efficient to restore intestinal homeostasis and ameliorate the progression of PD. We elucidate the underlying mechanism by which intestinal α-Syn triggers reactive oxygen species (ROS), and eventually leads to activation of the DUOX-ROS-JNK pathway. In addition, α-Syn from both guts and brains synergizes to accelerate the progress of PD. Conclusions These findings suggest that intestinal expression of α-Syn generates PD-like etiology, and induces dysbiosis that aggravates the progress of PD through the DUOX-ROS-JNK pathway in Drosophila, providing useful insights into the underlying etiology and pathogenesis of PD.