Study Rationale:
Our goal is to test whether Parkinson’s disease (PD) patients carrying a LRRK2 mutation have an abnormality in their lysosomes, a part of a cell that is necessary for degrading waste, toxins and abnormal proteins. Researchers hypothesize that correcting or enhancing lysosome activity would help protect brain cells from degeneration, slowing or stopping PD progression.
Hypothesis:
We hypothesize 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 toxic Lewy bodies).
Study Design:
First, we will examine nerve cells from PD patients in a dish. Some of these patients will have PD associated with a LRRK2 mutation, some associated with another type of mutation, and some with no clear reason at all (“sporadic”). We will obtain these nerve cells from living patients by using a new technique for turning skin or blood cells into nerve cells. Then we will see how well their lysosomes function in terms of ridding a cell of abnormal proteins (e.g., alpha-synuclein). We will also compare these findings with diseases that are known to be due to lysosomal abnormalities.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
We hope to identify drugs that might be used to restore function of the lysosome in PD patients and, hence, blunt disease progression.
Next Steps for Development:
If successful, we will next test whether any defects in lysosomal function are pharmacologically reversible, ideally by FDA-approved drugs that can be tested more quickly in clinical trials.