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.
As a major origin of evolutionary novelties, gene duplication is a widespread phenomenon across species. However, the evolutionary force that determines the fate of duplicate genes is still under debate. Here, we studied the functional evolution of duplicate genes at both macroevolution and microevolution scales using the genomic sequences of eleven Caenorhabditis species and 773 C. elegans wild isolates. We found that compared to older duplicate genes and single-copy genes, recently duplicated gene copies showed rapid turnover, large genetic diversity, and signs of balancing and positive selection within the species. Young duplicate genes have low basal expression restricted to a few tissues but show highly responsive expression towards pathogenic infections. Recently duplicated genes are enriched in chemosensory perception, protein degradation, and innate immunity, implicating their functions in enhancing adaptability to external perturbations. Importantly, we found that young duplicate genes are rarely essential, while old duplicate genes have the same level of essentiality as singletons, suggesting that essentiality develops over a long time. Together, our work in C. elegans demonstrates that natural selection shapes the dynamic evolutionary trajectory of duplicate genes.
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.
The phylotranscriptomic analysis of development in several species revealed the expression of older and more conserved genes in midembryonic stages and younger and more divergent genes in early and late embryonic stages, which supported the hourglass mode of development. However, previous work only studied the transcriptome age of whole embryos or embryonic sublineages, leaving the cellular basis of the hourglass pattern and the variation of transcriptome ages among cell types unexplored. By analyzing both bulk and single-cell transcriptomic data, we studied the transcriptome age of the nematode Caenorhabditis elegans throughout development. Using the bulk RNA-seq data, we identified the morphogenesis phase in midembryonic development as the phylotypic stage with the oldest transcriptome and confirmed the results using whole-embryo transcriptome assembled from single-cell RNA-seq data. The variation in transcriptome ages among individual cell types remained small in early and midembryonic development and grew bigger in late embryonic and larval stages as cells and tissues differentiate. Lineages that give rise to certain tissues (e.g., hypodermis and some neurons) but not all recapitulated the hourglass pattern across development at the single-cell transcriptome level. Further analysis of the variation in transcriptome ages among the 128 neuron types in C. elegans nervous system found that a group of chemosensory neurons and their downstream interneurons expressed very young transcriptomes and may contribute to adaptation in recent evolution. Finally, the variation in transcriptome age among the neuron types, as well as the age of their cell fate regulators, led us to hypothesize the evolutionary history of some neuron types.
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