Genome-wide screen identifies curli amyloid fibril as a bacterial component promoting host neurodegeneration
Chenyin Wang1, Chun Yin Lau1, Fuqiang Ma1
1School of Biological Sciences, The University of Hong Kong, Hong Kong Special Administrative Region, China.
Abstract:
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.
Insights
Gut bacteria influence neurodegenerative diseases. Researchers identified bacterial curli protein as a key factor promoting neuronal death in Parkinson's disease and other neurodegenerative conditions.
Area of Science:
- Microbiology
- Neuroscience
- Genetics
Background:
- Gut microbiota are increasingly linked to neurodegenerative disease progression.
- The precise molecular mechanisms of microbe-host interactions in neurodegeneration remain largely unknown.
Purpose of the Study:
- To identify bacterial genes influencing neurodegeneration using a genome-wide screen in *Caenorhabditis elegans*.
- To elucidate the role of specific bacterial components, particularly curli, in promoting neurodegeneration.
Main Methods:
- Conducted a genome-wide screen in *C. elegans* expressing human alpha-synuclein, feeding them *Escherichia coli* knockout mutants.
- Focused on the curli amyloid fibril, genetically deleting or pharmacologically inhibiting its major subunit, CsgA.
- Investigated curli's effect in *C. elegans* models of Alzheimer's, ALS, Huntington's disease, and human neuroblastoma cells.
Main Results:
- Identified 38 bacterial genes involved in pathways like curli formation, LPS assembly, and adenosylcobalamin synthesis that promote neurodegeneration.
- Deleting or inhibiting *E. coli*'s CsgA significantly reduced alpha-synuclein-induced neuronal death and improved neuronal function.
- Bacterial curli colocalized with alpha-synuclein within neurons, promoting aggregation via cross-seeding and exacerbating neurodegeneration across multiple disease models.
Conclusions:
- Bacterial curli amyloid fibrils are a critical factor driving neurodegeneration in Parkinson's disease and other neurological disorders.
- Targeting curli formation presents a potential therapeutic strategy for mitigating neurodegenerative diseases linked to gut microbiota dysbiosis.
Related Concept Videos
03:03Amyloid Fibrils
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining,...
03:03Amyloid Fibrils