Study Rationale: Parkinson's disease involves the generation of pathogenic proteins in the neurons, which trigger an immune response driven by inflammatory lymphocytes that infiltrate the brain and promote neuronal death. Moreover, recent studies have shown how the composition of the bacterial consortium residing in the gut represents a key factor triggering the development of Parkinson’s disease in genetically susceptible individuals. Specifically, short-chain fatty acids (SCFA), a type of substance produced by some bacteria residing in the gut, has been involved in the triggering of Parkinson’s disease development. Importantly, SCFA might induce an inflammatory function in gut lymphocytes.
Hypothesis: We hypothesize that the SCFA receptor present in lymphocytes, called GPR43, favors the generation of inflammatory lymphocytes in the gut, which are the responsible of the later inflammatory response in the brain of Parkinson’s disease individuals.
Study Design: To test this hypothesis, we will use a mouse model of Parkinson’s disease that develop the pathology depending on the presence of gut bacteria. First, we will determine the generation of inflammatory lymphocytes specific to pathogenic proteins in the gut and the brain. Secondly, we will evaluate the development of Parkinson’s disease in mice harboring lymphocytes genetically deficient in GPR43. Finally, we will assess the therapeutic potential of a drug that inhibits GPR43 on the development of the disease in this mouse model.
Impact on Diagnosis/Treatment of Parkinson’s disease: The potential results obtained in this project will provide new mechanistic knowledge explaining how the composition of gut bacteria and the immune system work together in triggering the development of Parkinson’s disease. Moreover, the potential results will show a new therapeutic target for the design of treatments to stop Parkinson’s disease development.
Next Steps for Development:If the inhibition of GPR43 using the drug results successful in mice, next steps will be testing the efficacy in other animal models of Parkinson’s disease. Subsequently, the therapeutic potential of GPR43 inhibition should be tested in human individuals with Parkinson's disease. Of note, the safety of the drug used to inhibit GPR43 here has already been validated in humans.