triggers α-synuclein pathology in the transgenic mouse model of PD.

Alpha-synuclein (α-syn) pathology is the hallmark of Parkinson's disease (PD). The leucine-rich repeat kinase 2 () gene is a major-effect risk gene for sporadic PD (sPD). However, what environmental factors may trigger the formation of α-syn pathology in carriers of risk variants are still unknown. Here, we report that a markedly increased abundance of (. ) in the intestinal microbiota was detected in risk variant(R1628P or G2385R) carriers with sPD compared with carriers without sPD. Animal experiments showed that . administration triggered pathological α-syn accumulation in the colon and spread to the brain via the gut-brain axis in R1628P mice, due to the co-occurrence of variant-induced inhibition of α-syn autophagic degradation and increased phosphorylation of α-syn caused by curli in . -derived extracellular vesicles. Fecal microbiota transplantation (FMT) effectively ameliorated motor deficits and α-syn pathology in R1628P mice. Our findings elaborate on the mechanism that triggers α-syn pathology in R1628P mice, and highlight a novel gene-environment interaction pattern in risk variants. Even more importantly, the findings reveal the interplay between the specific risk gene and the matched environmental factors triggers the initiation of α-syn pathology in sPD.