期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2106504118
关键词
Parkinson's disease; curli; neurodegeneration; microbe-host interaction
资金
- NIH Office of Research Infrastructure Programs [P40 OD010440]
- Food and Health Bureau of Hong Kong (Health and Medical Research Fund) [07183186]
- Research Grants Council of Hong Kong [27104219, C7026-20G]
- University of Hong Kong [201910159087]
This study reveals the critical role of gut microbiota in regulating neurodegenerative diseases, particularly through influencing the formation and aggregation of amyloid fibrils. This provides a new research direction for the treatment of neurodegenerative diseases.
Growing evidence indicates that gut microbiota play a critical role in regulating the progression of neurodegenerative diseases such as Parkinson's disease. The molecular mechanism underlying such microbe-host interaction is unclear. In this study, by feeding Caenorhabditis elegans expressing human alpha-syn with Escherichia coli knockout mutants, we conducted a genome-wide screen to identify bacterial genes that promote host neurodegeneration. The screen yielded 38 genes that fall into several genetic pathways including curli formation, lipopolysaccharide assembly, and adenosylcobalamin synthesis among others. We then focused on the curli amyloid fibril and found that genetically deleting or pharmacologically inhibiting the curli major subunit CsgA in E. coli reduced alpha-syn-induced neuronal death, restored mitochondrial health, and improved neuronal functions. CsgA secreted by the bacteria colocalized with alpha-syn inside neurons and promoted alpha-syn aggregation through crossseeding. Similarly, curli also promoted neurodegeneration in C. elegans models of Alzheimer's disease, amyotrophic lateral sclerosis, and Huntington's disease and in human neuroblastoma cells.
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