While inflammation of the brain caused by immune cells has been implicated in Parkinson’s disease (PD), it is unknown whether these cells attacking the brain initiate the disease. Moreover, there is new evidence that bacteria in the gut may actually trigger the immune system leading to disease initiation via the peripheral nerves that connect the gut with the brain. Our studies will integrate cutting-edge technologies in humans and pre-clinical models to determine whether the disease is mediated by immune cells recognizing alpha-synuclein, a key brain protein implicated in PD.
We hypothesize that in a subset of cases, PD is initiated by an autoimmune event involving recognition of alpha-synuclein in the gut, and that interactions between the immune system and the peripheral and central nervous systems establish the disease in the brain.
We propose integrating cutting-edge technologies in neuroimmunology, single cell genomics, gut microbiome and computational biology to determine at unprecedented depth whether PD has the signature of autoimmune processes and explore how immune reactions initiate a process, from the gut, that spreads through the peripheral nervous system and finally to the brain where neurodegeneration results in PD. First, we will characterize T cell-mediated autoimmunity in PD; second, we will evaluate the role of the microbiome in the initiation of PD and progression along the gut-to-brain axis; and third, we will define perturbations in the neuro-immune interactome in the PD brain.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
This work will reveal fundamental mechanisms that account for the initiation and progression of PD, uncovering disease- and tissue-specific profiles of autoreactive T cells and overall T cell surveillance that will lead to the discover of perturbed immune pathways in PD with potential application in the development of immunomodulatory therapies.
Next Steps for Development:
The successful completion of our proposed studies will identify key immune pathways in the onset of PD and determine whether to proceed with clinical trials using immunomodulatory drugs for PD. Such trials will aim to block the initiation of disease using immunosuppressive drugs in patients at risk of PD.