We investigate microbe–host interaction in the context of neurodegeneration by screening for Escherichia coli genes whose deletion alleviates Parkinson’s disease symptoms in the nematode Caenorhabditis elegans overexpressing human α-synuclein (α-syn, A53T). The screen yields 38 E. coli genes that promote neurodegeneration. Two of these genes, csgA and csgB, code for proteins that form curli, one type of bacterial amyloid fibers. Curli cross-seeds and colocalizes with α-syn both in C. elegans neurons and human neuroblastoma cells. Curli-induced α-syn aggregations down-regulate mitochondrial genes, causing energy failure in neurons. Moreover, we found that curli may have general effects in promoting neuropathologies induced by different aggregation-prone proteins, such as A-β in Alzheimer’s disease, Huntingtin in Huntington’s disease, and SOD1 in amyotrophic lateral sclerosis.
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.