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

Descripción del proyecto

Estudio de la implicación de la microbiota intestinal en el inicio y la progresión de la enfermedad de Parkinson

Se ha observado que, en la enfermedad de Parkinson (EP), los síntomas gastrointestinales aparecen años antes de que se desarrollen síntomas motores. Estudios recientes han revelado la correlación entre los cambios de composición en la microbiota intestinal y los síntomas de la EP. Comprender los mecanismos mediante los cuales las bacterias interactúan con el hospedador para afectar al sistema nervioso puede llevar al descubrimiento de nuestras estrategias de pronóstico y tratamiento para esta enfermedad. El modelo de agregación de proteínas de la EP en «Caenorhabditis elegans» muestra un potente efecto protector de una bacteria probiótica humana contra la agregación de α-sinucleína, un indicio bien establecido de la EP. El proyecto financiado con fondos europeos Gut_Fights_PD tiene por objeto arrojar luz sobre los mecanismos a través de los cuales las bacterias probióticas actúan para proteger frente a la agregación de α-sinucleína y la naturaleza de la respuesta inducida en el nematodo.

Objetivo

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.