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

Abstract

Growing evidence indicate that gut microbiota play a critical role in regulating the progression of neurodegenerative diseases, such as Parkinson's disease (PD). The molecular mechanism underlying such microbe-host interaction is unclear. In this study, by feeding C. elegans expressing human α-syn with E. 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, adenosylcobalamin biosynthesis 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 AD, ALS, and HD and in human neuroblastoma cells.

Metagenomics of Parkinson’s disease implicates the gut microbiome in multiple disease mechanisms

“…In another genetic model of PD (Pink1 -/-), intestinal infection with Gram-negative bacterial pathogens was shown to elicit an immune reaction that leads to neuronal degeneration and motor deficits, and which can be reversed with the PDmedication, L-dopa 13 . In addition, we and others have found that, curli, an amyloidogenic protein produced by Gram-negative Escherichia coli, induces alpha-synuclein aggregation and accelerates disease in the gut and neurodegeneration in the brain [14][15][16] . We have detected overabundance of opportunistic pathogens in the gut microbiomes of individuals with PD 17 .…”

Metagenomics of Parkinson’s disease implicates the gut microbiome in multiple disease mechanisms

“…In another genetic model of PD (Pink1 -/-), intestinal infection with Gram-negative bacterial pathogens was shown to elicit an immune reaction that leads to neuronal degeneration and motor deficits, and which can be reversed with the PD-medication, L-DOPA 16 . In addition, we and others have found that, curli, an amyloidogenic protein produced by Gram-negative Escherichia coli, induces alpha-synuclein aggregation and accelerates disease in the gut and neurodegeneration in the brain [17][18][19] . We have detected overabundance of opportunistic pathogens in the gut microbiomes of individuals with PD 20 .…”

“…The bacterial-derived amyloidogenic protein, curli, exacerbates alpha-synuclein pathology and inflammation in experimental models of PD [17][18][19] . Many Enterobacteriaceae species encode curli 56 .…”

Myotubularin-related protein protects against neuronal degeneration mediated by oxidative stress or infection

“…C. elegans is an attractive model to study neurodegenerative diseases because of its distinctive attributes, such as the well-characterized genetic toolsets and the mapping of the organism's entire neural wiring of the organism (11). Moreover, studies in C. elegans have demonstrated the role of pathogens in inducing neural changes considered hallmarks of neurodegeneration (12)(13)(14)(15).…”