This grant builds upon the research from a prior grant: The Genome-Microbiome Axis in the Cause of Parkinson Disease: Mechanistic Insights and Therapeutic Implications from Experimental Models and a Genetically Stratified Patient Population
Study Rationale: Recent studies suggest that the alpha-synuclein protein that forms aggregates in Parkinson’s disease (PD) may originate in the gut and travel along nerves that go to the brain. Intestinal bacteria play a key role in inflammation and boost gut alpha-synuclein. Mutations in GBA, the gene encoding glucocerebrosidase, increase alpha-synuclein and are common in PD. However, only about a third of people with GBA mutations get PD. We will examine gut bacteria, inflammation, alpha-synuclein and GBA to assess why people with GBA mutations develop PD and to examine whether the same factors can cause PD in those without GBA mutations.
Hypothesis: We hypothesize that both genes and gut bacteria contribute to PD risk. We will examine people with GBA mutations to determine whether their risk for PD is enhanced by their intestinal bacteria and whether these bacteria facilitate the movement of alpha-synuclein from the gut to the brain.
Study Design: Using oral and fecal samples, we will identify bacteria that may be unique to people with mutations in GBA and assess how these microbes might increase alpha-synuclein and cause PD. We will also use preclinical models to study the changes that link the bacteria and inflammation to alpha-synuclein and its spread from the gut to the brain. Lastly, we will determine whether altering the microbiome can prevent alpha-synuclein going to the brain.
Impact on Diagnosis/Treatment of Parkinson’s disease: If successful, we will be able to identify and treat the individuals with GBA mutations who are most likely to get PD. We also think that this treatment may help prevent PD in people with other genetic risk factors.
Next Steps for Development: We will first test the changes to bacteria in our preclinical models using antibiotics and assess whether they stop alpha-synuclein going to the brain and reduce inflammation. Use of medicines that already have clinical approval will facilitate the development of a new treatment for PD.