Protein conformational diseases (PCDs) are characterized by a progressive loss of neuronal or muscle function due to protein misfolding and aggregation, a common feature among diseases such as Alzheimer's, Parkinson's, Huntington's, or Lou Gehrig's disease. The exact factors that influence PCDs are not known. Recent evidence suggests that bacteria may contribute to the pathogenesis of these neurodegenerative diseases. To better understand the influence of bacteria on protein homeostasis (proteostasis), we are studying the effect of bacterial colonization of the Caenorhabditis elegans gut on protein aggregation in the intestine and other tissues. In a screen of 52 of the most common human pathogenic-commensal bacteria, we found two Gram-negative species, Pseudomonas aeruginosa and Klebsiella pneumoniae, that enhanced protein aggregation in the intestine by nearly five-fold; these two strains also affect protein aggregation in the muscle. Both species are part of the normal human microbiome and are known opportunistic pathogens. An increase in the abundance of these bacteria within the human gut was previously linked with the enhanced progression of neurodegenerative diseases. Collectively, these results suggest that intestinal bacteria affect the host folding environment; however, which bacterial factors are responsible for the enhancement of aggregation remains unknown. As such, we propose to screen genome-wide mutant libraries of P. aeruginosa and K. pneumoniae for genes that will abolish the enhancement of protein aggregation upon colonization of the C. elegans intestine. Identification of bacterial genes and pathways that are responsible for disruption of host proteostasis will provide a new mechanistic understanding of host-bacteria interaction that can provide a basis for the development of prophylactics, therapeutics, and biomarkers for PCDs.
There is no cure nor effective treatment for protein conformational diseases, such as Alzheimer's or Parkinson's, mainly because it is not known what causes these conditions. Recently, it was discovered that dysbiosis of the human gut microbiota contributes to the onset and progression of neurodegenerative diseases, but the underlying mechanisms remain unknown. We propose to identify bacterial genes that contribute to the disruption of host proteostasis, ultimately leading to toxic protein aggregation.
