Study Rationale: Parkinson’s disease (PD) has been associated with a dysregulation of cholesterol metabolism in brain cells and the accumulation of a protein called alpha-synuclein. Our research is aimed at identifying how cholesterol and its metabolites may contribute to the risk of developing PD. We have collected preliminary data showing that the interaction of a cholesterol metabolite with alpha-synuclein can severely deregulate normal function of human brain cells.
Hypothesis: We hypothesize that an interaction between cholesterol or it metabolites and the protein alpha-synuclein can cause a dysfunction of otherwise healthy brain cells.
Study Design: We will begin by addressing how normal neuronal function is disturbed by the addition of cholesterol or its metabolites in the presence of alpha-synuclein. We will then investigate how cholesterol and its metabolites are taken up by cells and how, in combination with alpha-synuclein, they cause PD-like symptoms in cells. In particular, we will address, whether this interaction causes defects in different cellular organelles, disturbs the cholesterol metabolism or leads to an increase in alpha-synuclein aggregation.
Impact on Diagnosis/Treatment of Parkinson’s disease: If successful, our study will provide new therapeutic avenues to treat PD, novel biomarkers for monitoring cholesterol metabolism and cellular defects in peripheral cells from people with PD and potential diagnostics for assessing disease risk, progression and response to therapy.
Next Steps for Development: Progress towards clinical application of our results would involve additional studies of cholesterol- or metabolite-reducing drugs, drugs that prevent alpha-synuclein from interacting with cholesterol or its metabolites, drugs that strengthen normal cellular function or drugs that prevent the uptake of cholesterol and its metabolites bound to alpha-synuclein.