Exploring the Impacts of the Human Microbiota in C. Elegans Models of Parkinson's Disease

Abstract

The human gastrointestinal tract is home to a community of trillions of microorganisms, predominantly bacteria, collectively known as the gut microbiota. The role of the gut microbiota in human health and disease has become increasingly apparent, with microbiotal dysbiosis being linked to many disorders, including Parkinson’s Disease (PD). PD is a common complex neurodegenerative disorder characterized by selective degeneration of dopaminergic neurons in the substantia nigra pars compacta and accumulation of alpha-synuclein enriched protein aggregates within neurons. Obvious genetic causes are detected in only 5-10% of cases, suggesting that environmental factors, like the microbiota, play a major role in its development. However, despite accumulating evidence linking the gut microbiota to PD, minimal work has successfully identified causal mechanisms between bacterial molecules and the neurodegenerative process. In order to identify the relationship between human gut commensals and PD pathophysiology, we applied a single-bacterium approach, using the nematode Caenorhabditis elegans as a gnotobiotic model. Animals expressing disease-associated G2019S mutant human leucine-rich repeat kinase (LRRK2) protein in dopaminergic neurons were employed as a model of neurodegeneration to systematically test 57 bacteria representative of the human gut microbiota to identify gut commensals able to modulate PD pathophysiology. We identified a microbiotal isolate, Actinomyces viscosus, able to reduce LRRK2-mediated neurodegeneration and alpha-synuclein aggregation in a synucleinopathy model. Global gene expression analysis via RNA sequencing revealed increased expression of C. elegans aspartic cathepsins in response to neuroprotective A. viscosus. Monitoring autophagic markers confirmed that A. viscosus suppresses autophagic dysfunction associated with pathogenic LRRK2 expression. RNAi-mediated and genetic knockdown of identified aspartic cathepsins induced neurodegeneration in the LRRK2 transgenic model, confirming their implication in neuronal health. Our findings contribute to the current understanding of how the gut microbiota can influence host physiology in the context of PD, elucidating a potential mechanism of microbiota-mediated neuroprotection.