The gut-brain axis plays a vital role in Parkinson’s disease (PD). The mechanisms of gut-brain transmission mainly focus on α-synuclein deposition, intestinal inflammation and microbiota function. A few studies have shown the trigger of PD pathology in the gut. α-Synuclein is highly conserved in food products, which was able to form β-folded aggregates and to infect the intestinal mucosa. In this study we investigated whether α-synuclein-preformed fibril (PFF) exposure could modulate the intestinal environment and induce rodent models replicating PD pathology. We first showed that PFF could be internalized into co-cultured Caco-2/HT29/Raji b cells in vitro. Furthermore, we demonstrated that PFF perfusion caused the intestinal inflammation and activation of enteric glial cells in an ex vivo intestinal organ culture and in an in vivo intestinal mouse coloclysis model. Moreover, we found that PFF exposure through regular coloclysis induced PD pathology in wild-type (WT) and A53T α-synuclein transgenic mice with various phenotypes. Particularly in A53T mice, PFF induced significant behavioral disorders, intestinal inflammation, α-synuclein deposition, microbiota dysbiosis, glial activation as well as degeneration of dopaminergic neurons in the substantia nigra. In WT mice, however, the PFF induced only mild behavioral abnormalities, intestinal inflammation, α-synuclein deposition, and glial activation, without significant changes in microbiota and dopaminergic neurons. Our results reveal the possibility of α-synuclein aggregates binding to the intestinal mucosa and modeling PD in mice. This study may shed light on the investigation and early intervention of the gut-origin hypothesis in neurodegenerative diseases.
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This study was supported by grants from the National Science & Technology Major Project “Key New Drug Creation and Manufacturing Program”, China (2018ZX09711002–003–013), and the Scientific Innovation Project of the Chinese Academy of Sciences (XDA12040304 and XDA12040216). This project was supported by the Shanghai Committee of Science and Technology, China (18DZ2290200), and the grants from National Natural Science Foundation of China (No. 82104140, 32171220).
The authors declare no competing interests.
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Yang, Zx., Zhang, Y., Wang, Q. et al. Addition of α-synuclein aggregates to the intestinal environment recapitulates Parkinsonian symptoms in model systems. Acta Pharmacol Sin (2023). https://doi.org/10.1038/s41401-023-01150-2