Our goal is to test whether people with Parkinson’s disease (PD) who carry a LRRK2 mutation (compared to those carrying another genetic PD-predisposing mutation or people with sporadic PD) have an abnormality in their lysosomes, a part of a cell that is necessary for ridding that cell of waste, toxins, abnormal proteins and breakdown material. If that is the case, then this problem might be reversible with drugs that restore a degree of normal lysosomal function and hence blunt PD progression and perhaps reverse some symptoms.
We hypothesize that PD is, at least in part, a “lysosom-opathy” and that mutated LRRK2 creates or worsens malfunction of lysosomes resulting in the mishandling and export of toxic proteins (e.g., alpha-synuclein, the material that comprises Lewy bodies).
First, we will examine nerve cells from PD patients. Some will have PD because of a LRRK2 mutation, some by another type of mutation, and some for no clear reason at all (“sporadic”). The way we will obtain these nerve cells from living patients is to use a new technique for turning skin or blood cells into nerve cells. Then we will see how well their lysosomes function in ridding a cell of abnormal proteins (e.g., alpha-synuclein). To make sure that any defect we observe is really due to the LRRK2 mutation, we will introduce those abnormalities into normal and other PD nerve cells to see whether the defects can be recreated or worsened. We will also compare these findings with diseases that are known to be due to lysosomal abnormalities. It is interesting that some patients with lysosomal disorders have a higher propensity for PD.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
We hope to identify drugs — perhaps some already approved by the FDA — that might be used to restore function of the lysosome in PD patients and, hence, blunt disease progression, or even reverse some symptoms.
Next Steps for Development:
Given that many of our read-outs can form the basis for drug discovery studies, we will next test whether any defects in lysosomal function are pharmacologically reversible, ideally by already FDA-approved drugs that can be used quickly in clinical trials.