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

Descrizione del progetto

Lo studio del coinvolgimento del microbiota intestinale nell’insorgenza e nella progressione del morbo di Parkinson

È stato osservato che nel morbo di Parkinson i sintomi gastrointestinali compaiono anni prima rispetto allo sviluppo dei sintomi motori. Recenti studi hanno rivelato la correlazione tra i cambiamenti nella composizione del microbiota intestinale e i sintomi del morbo di Parkinson. Comprendere i meccanismi del modo in cui i batteri interagiscono con l’ospite per condizionare il sistema nervoso potrebbe condurre a nuove strategie prognostiche e diagnostiche per il trattamento del morbo di Parkinson. Il modello di aggregazione proteica del morbo di Parkinson all’interno di Caenorhabditis elegans mostra un forte effetto protettivo di un batterio probiotico umano contro l’aggregazione di α-sinucleina, un elemento caratteristico consolidato di questa malattia. Il progetto Gut_Fights_PD, finanziato dall’UE, si propone di chiarire i meccanismi attraverso cui i batteri probiotici agiscono per proteggersi dall’aggregazione di α-sinucleina e la natura della risposta indotta nel nematode.

Obiettivo

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.