Investigating protective mechanisms of gut bacteria in C. elegans models of Parkinson’s disease

Description du projet

Étude de l’implication du microbiote intestinal dans l’apparition et la progression de la maladie de Parkinson

Des observations ont révélé que, dans la maladie de Parkinson (MP), les symptômes gastro-intestinaux apparaissent des années avant le développement des symptômes moteurs. Selon des études récentes, il y a une corrélation entre les changements de composition du microbiote intestinal et les symptômes de la maladie de Parkinson. La compréhension des mécanismes de l’interaction des bactéries avec l’hôte pour affecter le système nerveux peut conduire à de nouvelles stratégies pronostiques et thérapeutiques pour le traitement de la maladie de Parkinson. Le modèle d’agrégation des protéines de la MP chez C. elegans révèle l’effet protecteur considérable d’une bactérie probiotique humaine contre l’agrégation de l’α-synucléine, un signe bien établi de la MP. Le projet Gut_Fights_PD, financé par l’UE, vise à faire la lumière sur les mécanismes par lesquels la bactérie probiotique agit pour protéger de l’agrégation des α-synucléines et sur la nature de la réponse induite chez le nématode.

Objectif

The recent discovery that the composition of the gut microbiota can influence the symptoms of neurodegenerative diseases is a paradigm shift in how we view these conditions. In Parkinson’s disease (PD), patients frequently experience gastrointestinal symptoms years before the development of motor deficits and recent studies reveal clear alterations in the gut microbiota composition at advanced stages, which correlate with severity of their symptoms. Therefore, understanding the molecular mechanisms by which gut bacteria interact with the host to affect the nervous system may uncover novel prognostic and therapeutic strategies for neurological diseases. To address this gap of knowledge, we propose a single bacteria-worm model as a genetically tractable system to mechanistically investigate the connection between bacterial metabolites produced in the gut and neurodegeneration. Preliminary data from the lab on a protein aggregation model of PD in C. elegans, show a strong protective effect of a human probiotic bacterial species on α-synuclein aggregation, a well-established factor in Parkinson’s disease. The aim of this project is to understand the mechanisms through which the probiotic bacteria act to protect from α-syn aggregation and the nature of the response induced in the nematode. We are proposing a bidirectional strategy, manipulating genetically both players in this interaction, the bacteria and the nematode. Using a candidate molecular approach based on available data and an unbiased high-throughput analysis, we expect to elucidate new metabolic pathways employed by the bacteria to modulate protein aggregation as well as the molecular mechanisms that elicit this response in the nematode. By directly testing on various C. elegans models of PD the pharmacological effect of the discovered beneficial metabolites, we will identify specific neuroprotective compounds with future therapeutic potential.