Parkinson's disease (PD) affects nearly any body system, as evidenced by the diversity of its symptoms. While its non-motor symptoms, such as olfactory dysfunction, rapid eye movement sleep behavior disorder (RBD) and gastrointestinal (GI) abnormalities, do not define the disease, they have a large impact on those living with it. In this project, we will use a pre-clinical model of Parkinson's with GI symptoms that mirror those experienced by people with PD. This model harbors irregular alpha-synuclein, the sticky protein that clumps in the cells of people with Parkinson's disease. Using this model, we can learn whether disabling the LRRK2 protein -- the greatest known contributor to inherited PD -- improves the GI symptoms. This work will expand our understanding of PD by providing further insight into its non-motor symptoms and identify new strategies for the management of those symptoms.
We aim to determine whether disabling the LRRK2 protein with drugs relieves the GI symptoms of PD in an alpha-synuclein-induced pre-clinical model with Parkinson's symptoms.
For six months, pre-clinical models will be treated with a drug that blocks the activity of LRRK2, disabling the protein. We will assess the effects of the treatment on the GI function, LRRK2 activity and amount of alpha-synuclein.
Impact on Diagnosis/Treatment of Parkinson's disease:
If the LRRK2-disabling drug relieves the GI symptoms in the pre-clinical model, we will have determined a way to improve a specific patient-related outcome. It will also establish a link between the LRRK2 and alpha-synuclein in Parkinson's disease.
Next Steps for Development:
The next step would be to validate the study by creating new pre-clinical models of inherited PD with changes in two genes, including the LRRK2 gene, to test whether PD symptoms in these models are more severe. It would also be valuable to create a pre-clinical model with genetically disabled LRRK2 and another model that is resistant to drugs that disable LRRK2 to confirm the present study findings.