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ABSTRACT
Alpha-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.
Acknowledgments
We thank all our collaborators at the First Affiliated Hospital of ZZU for their assistance with the transendoscopic enteral tubing and patient sample collection. Specifically, we thank Prof. Shilin Gao and for his excellent technical support. We acknowledge assistance with the access of analytic instruments from Translational Medicine Center at The First Affiliated Hospital of Zhengzhou University.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Author contributions
X.W. conceived and designed the experiments; X.W., X.D., and B.T. coordinated the whole project; X.D. and J.T. were responsible for the initial assessing and diagnosing patients; D.L., R.F. and R.Z. were responsible for assessing, documenting their patients’ health information; R.J. and J.W. recorded and confirmed the data; H.L. and C.Q. conducted modeling surgery and harvested the samples; H.L. and Y.C. performed the animal behavioral tests; J.Z. and J.W. performed immunostainings and western blot experiments; Y.C. and R.F. performed the ELISA experiments; X.W. and X.D. provided statistical analysis and technical support; X.W., X.D., and B.T. participated in final data analysis and interpretation; X.W., X.D., and D.L. did most of the writing with input from other authors; all of the authors discussed the results and commented on the manuscript.
Data availability statement
Metagenomic data were analyzed using custom software that is available at CRAN (https://cran.r-project.org/web/packages/pheatmap/index.html, http://CRAN.R-project.org/package=ggplot2). All relevant data supporting the findings of this study are either included within the article and its Additional Information files or are available upon request from the corresponding author. The mouse model will be made available on request.
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2023.2276296
Correction Statement
This article has been corrected with minor changes. These changes do not impact the academic content of the article.