Study Rationale:
Changes (mutations) in the GBA1 gene cause Gaucher disease, a rare condition that causes fatty substances to build up and organs to swell, and increase the risk of Parkinson's disease (PD). The GBA1 gene directs the production of an enzyme called glucocerebrosidase, which breaks down glucosylceramide lipids (fatty substances) inside cells. We have previously shown that lipids accumulate in nerve cells and cause damaging changes, such as alpha-synuclein protein clumping. In this project, we aim to determine if reducing lipid buildup can also reduce protein clumping and improve nerve cell function in pre-clinical models.
Hypothesis:
We hypothesize that reducing lipid buildup will prevent the production or increase the breakdown of protein clumps and restore the function of nerve cells.
Study Design:
We will use pre-clinical models of Gaucher disease that build up lipid stores in their cells and treat these models with lipid-reducing drugs at different doses. We will then determine if this lipid-reducing treatment can ameliorate disease-causing changes in these cells. We will correlate the levels of lipid reduction at each dose with changes in protein clumps, brain cell death and movement of the models.
Impact on Diagnosis/Treatment of Parkinson's Disease:
Lipid-reducing therapeutic agents are currently in clinical trials for GBA1-related PD. The findings of this study will provide critical information about the development of these agents in future clinical trials. At the end of the project, we aim to have determined the degree of lipid reduction required to reverse disease-related changes, providing a target for future clinical trials.
Next Steps for Development:
Using a combination of cell and pre-clinical models, we will continue to develop more effective lipid-reducing agents and metrics that can be used to accurately predict therapeutic efficacy in clinics.