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

Background: Aberrant aggregation of alpha-synuclein (alpha-syn) is a key pathological feature of Parkinson's disease (PD), but the precise role of intestinal alpha-syn in the progression of PD is unclear. In a number of genetic Drosophila models of PD, alpha-syn was frequently ectopically expressed in the neural system to investigate the pathobiology. Method: We investigated the potential role of intestinal alpha-syn in PD pathogenesis using a Drosophila model. Human alpha-syn was overexpressed in Drosophila guts, and life span, survival, immunofluorescence and climbing were evaluated. Immunofluorescence, Western blotting and reactive oxygen species (ROS) staining were performed to assess the effects of intestinal alpha-syn on intestinal dysplasia. High-throughput RNA and 16S rRNA gene sequencing, quantitative RT-PCR, immunofluorescence, and ROS staining were performed to determine the underlying molecular mechanism. Results: We found that the intestinal alpha-syn alone recapitulated many phenotypic and pathological features of PD, including impaired life span, loss of dopaminergic neurons, and progressive motor defects. The intestine-derived alpha-syn disrupted intestinal homeostasis and accelerated the onset of intestinal ageing. Moreover, intestinal expression of alpha-syn induced dysbiosis, while microbiome depletion was efficient to restore intestinal homeostasis and ameliorate the progression of PD. Intestinal alpha-syn triggered ROS, and eventually led to the activation of the dual oxidase (DUOX)-ROS-Jun N-terminal Kinase (JNK) pathway. In addition, alpha-syn from both the gut and the brain synergized to accelerate the progression of PD. Conclusions: The intestinal expression of alpha-syn recapitulates many phenotypic and pathologic features of PD, and induces dysbiosis that aggravates the pathology through the DUOX-ROS-JNK pathway in Drosophila. Our findings provide new insights into the role of intestinal alpha-syn in PD pathophysiology.