Emerging evidence supports the concept that alpha-synuclein pathology, a hallmark of Parkinson’s disease (PD), might originate in the gastrointestinal tract and spread to the brain. However, where and how pathological alpha-synuclein initially forms remains unclear. Certain gut microbiota and some environmental toxins have been associated with PD. We recently discovered that specialized sensory cells in the gut known as enteroendocrine cells (EECs), in direct contact with gut microbiota and different environmental toxins, might transfer misfolded alpha-synuclein to the nervous system in disease.
We propose that gut microbes and environmental toxins, alone or in combination, corrupt alpha-synuclein protein expressed in EECs to misfolded pathological forms that might spread to the nervous system in a novel circuit important in PD.
Using a unique, large, and well-characterized collection of human data, we will identify potential triggers and alterations in gut microbiota and neuroinflammatory pathways that are associated with PD. We will test known and experimental triggers (toxins and microorganisms) in two complementary model systems (ex vivo cultures, and in vivo in mice) to determine effects on the formation and spread of pathological alpha-synuclein within a predictable circuit of interconnected cells vulnerable to disease.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
These studies will (1) establish how EECs are involved in the formation of pathological alpha-synuclein at the earliest stages of disease, (2) identify gut-associated toxins and microbes that contribute to PD, (3) develop novel “humanized” pre-clinical model systems, and (4) test two particularly promising experimental therapeutic approaches in the novel model systems.
Next Steps for Development:
Once the toxins and microbes are identified, the mechanism(s) involved will be investigated in detail to devise strategies for targeting the microbiome to prevent induction of alpha-synuclein pathology in order to prevent or stop progression of PD. Second, our pre-clinical humanized mouse model will be shared broadly with the PD field to enable others to test additional experimental therapeutic strategies.