Study Rationale:
Why do some people develop Parkinson’s disease (PD) while others do not? Although many genetic risk factors have been identified, we still cannot confidently answer this question, or explain how certain cells in our brain go from being healthy early in life to diseased in old age. Clearly, numerous complex factors are involved, and a systematic investigation of the key cellular and molecular players is necessary to understand and effectively treat this disease.
Hypothesis:
We hypothesize that single genetic factors are insufficient to cause PD — rather, that it is triggered by a combination of genetics, age-related factors and their effects in different brain cells.
Study Design:
Here we propose to dissect the genetic, age-related and cell-type-specific factors that lead to PD using a collection of genetically diverse stem cells derived from patients. Using advanced methods pioneered by our team, we will convert these stem cells into the different types of brain cells implicated in PD — neurons, microglia and astrocytes — allowing us to investigate how genetic risk factors, the aging process and these different cell types interact to trigger disease. We will assess how various combinations of these factors disrupt the function of brain cells using detailed molecular studies, microscopy, genetic manipulations and biochemical measurements — building a computational network model of the factors that cause PD.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
This richer, fully human cell model of PD will provide an entirely new level of understanding of how the interplay between genetics, different brain cells and aging shapes individual disease risk, enabling early diagnosis, prediction of therapeutic targets that could halt or reverse the disease, and stratification of patients into therapeutically meaningful subgroups.