Study Rationale: More than 100 regions of the chromosomes that we inherit from our parents show differences in DNA sequence between people with and without Parkinson’s disease (PD). Furthermore, as we age, new, non-inherited DNA mutations can also arise. However, we don't fully understand how these inherited and new DNA changes increase the risk of PD. Although PD mainly affects the brain, evidence suggests that it might begin in the gut and later move to the brain, but the cells and pathways involved are not clear.
Hypothesis: We hypothesize that DNA variants can alter the activity of certain genes in particular cells of the brain and the gut, which in turn increases the risk of developing PD.
Study Design: We previously sequenced the DNA and RNA (the intermediate molecule through which DNA acts) from more than 3 million single cells in the brain and gut of hundreds of healthy individuals and people with PD. Now, we will determine which DNA variants change the expression of disease-relevant genes, and we will characterize how they do so and in which type of brain or gut cells they act. To analyze how the DNA variants alter the functioning of these specific cell types, we will apply analytical methods, including artificial intelligence, and confirm our results in studies of human cells and preclinical models.
Impact on Diagnosis/Treatment of Parkinson’s disease: Understanding how DNA variants change the functioning of specific cells in the brain and gut, including the activity of specific genes, will provide insight into the development of PD with value for translation to the clinic.
Next Steps for Development: By identifying genes that increase the risk of PD in the brain and gut, and determining how their activity is regulated in health and in PD, we will improve the understanding of how PD progresses, knowledge that can contribute to the development of new and more effective targeted treatments.