Coordinating Lead PI: Professor Anthony Schapira (UCL)
Co-Investigators and Collaborators: Prof Fabio Blandini, Prof Donato Di Monte, Dr Michela Deleidi, Prof Stanislav Ehrlich, Dr Jane Macnaughtan and Prof Hervé Blottière
Project Manager: Sofia Koletsi
Team Schapira's ASAP-MJFF funded project is part of the Neuro-immune Interactions branch of the ASAP Collaborative Research Network (CRN). The project aims to investigate the interplay between specific microbiome signatures and genetic predispositions (with a focus on GBA mutations) in the cause of Parkinson's disease.
The project is based on an international effort with renowned collaborators led by UCL, namely the IRCCS Mondino Foundation in Italy, the National Research Institute for Agriculture, Food and the Environment (INRAE) in France as well as the German Centre for Neurodegenerative Diseases (DZNE).
Mutations in the gene for glucocerebrosidase (GBA) increase alpha-synuclein expression and are common in Parkinson disease (PD). However, only about a third of people with GBA mutations get PD. Research suggests that the increase in the alpha-synuclein protein associated with PD may come from the gut and travel along nerves that go to the brain. The microbiome environment, including an increase in gut alpha-synuclein and inflammation, may be a causal link between GBA mutations and PD.
We think that the combination of one’s genetic makeup and microbiome are important in their risk for getting PD. We will look at people with GBA mutations to see if their risk for PD is caused by their gut bacteria, and to see if their bacteria increase alpha-synuclein transport from gut to brain.
We will use mouth and fecal samples from people with GBA-PD to identify the bacteria special to them and how these might increase alpha-synuclein and cause PD. We will also use special lab models (mouse models, iPSCs and 3D organoids) to study the changes that link the bacteria and inflammation to alpha-synuclein and its spread from the gut to the brain. We will explore methods to change the bacterial composition of the microbiome to see if this can stop alpha-synuclein transport to the brain.
Impact on Diagnosis/Treatment of Parkinson’s Disease
This research may provide insight into which GBA mutations carriers are most likely to get PD and whether bacterial profile changes will alter alpha-synuclein transport. Being able to predict PD onset may allow us to find a treatment window to prevent disease onset altogether. Further, this research may open more avenues for drug repurposing to find compounds that alter microbiome composition in ways that are beneficial for halting alpha-synuclein transport.