Escherichia coli triggers α-synuclein pathology in the LRRK2 transgenic mouse model of PD
Dongxiao Liang,
Han Liu,
Ruoqi Jin,
Renyi Feng,
Jiuqi Wang,
Chi Qin,
Rui Zhang,
Yongkang Chen,
Jingwen Zhang,
Junfang Teng,
Beisha Tang,
Xuebing Ding,
Xuejing Wang
Affiliations
Dongxiao Liang
Department of Neurology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
Han Liu
Department of Neurology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
Ruoqi Jin
Department of Neurology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
Renyi Feng
Department of Neurology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
Jiuqi Wang
Department of Neurology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
Chi Qin
Department of Neurology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
Rui Zhang
Department of Neurology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
Yongkang Chen
Department of Neurology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
Jingwen Zhang
Department of Neurology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
Junfang Teng
Department of Neurology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
Beisha Tang
Department of Neurology, Multi-Omics Research Center for Brain Disorders, the First Affiliated Hospital, University of South China, Hengyang, Hunan, China
Xuebing Ding
Department of Neurology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
Xuejing Wang
Department of Neurology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
ABSTRACTAlpha-synuclein (α-syn) pathology is the hallmark of Parkinson‘s disease (PD). The leucine-rich repeat kinase 2 (LRRK2) 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 LRRK2 risk variants are still unknown. Here, we report that a markedly increased abundance of Escherichia coli (E. coli) in the intestinal microbiota was detected in LRRK2 risk variant(R1628P or G2385R) carriers with sPD compared with carriers without sPD. Animal experiments showed that E. coli administration triggered pathological α-syn accumulation in the colon and spread to the brain via the gut-brain axis in Lrrk2 R1628P mice, due to the co-occurrence of Lrrk2 variant-induced inhibition of α-syn autophagic degradation and increased phosphorylation of α-syn caused by curli in E. coli-derived extracellular vesicles. Fecal microbiota transplantation (FMT) effectively ameliorated motor deficits and α-syn pathology in Lrrk2 R1628P mice. Our findings elaborate on the mechanism that E. coli triggers α-syn pathology in Lrrk2 R1628P mice, and highlight a novel gene-environment interaction pattern in LRRK2 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.
