Genome-wide screen identifies curli amyloid fibril as a bacterial component promoting host neurodegeneration

• Published in: Proceedings of the National Academy of Sciences - PNAS 2021-08, Vol.118 (34), p.1-12
• Main Authors: Lau, Chun Yin, Ma, Fuqiang
• Format: Article
• Language: English
• Subjects: Adenosylcobalamin; alpha-Synuclein - chemistry; alpha-Synuclein - genetics; alpha-Synuclein - metabolism; Alzheimer's disease; Amyloid - chemistry; Amyotrophic lateral sclerosis; Animals; Bacteria; Biofilms - growth & development; Biological Sciences; Caenorhabditis elegans; E coli; Escherichia coli; Escherichia coli - physiology; Escherichia coli Proteins - genetics; Escherichia coli Proteins - metabolism; Genes; Genome, Bacterial; Genome-Wide Association Study; Genomes; Host Microbial Interactions; Humans; Huntington's disease; Huntingtons disease; Intestinal microflora; Lipopolysaccharides; Microbiota; Mitochondria; Movement disorders; Neuroblastoma; Neuroblasts; Neurodegeneration; Neurodegenerative diseases; Neurodegenerative Diseases - etiology; Neurodegenerative Diseases - metabolism; Neurodegenerative Diseases - pathology; Parkinson's disease
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2106504118

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 α-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 α-syn–induced neuronal death, restored mitochondrial health, and improved neuronal functions. CsgA secreted by the bacteria colocalized with α-syn inside neurons and promoted α-syn aggregation through cross-seeding. 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.