Study Rationale:
Mutations in the LRRK2 gene are the most common inherited cause of Parkinson’s disease. These changes affect how cells read and process genetic messages, producing different versions of mRNAs and proteins called isoforms. Some of these isoforms may not work properly, disrupting important pathways in brain cells. We recently found that one LRRK2 mutation changes mRNA isoforms in the brain. In this project, we will study several disease-causing mutations in LRRK2 to see which isoforms are most affected. We will then test what these altered isoforms do in cells and whether they can also be detected in blood samples from patients.
Hypothesis:
We believe LRRK2 mutations alter how cells make different versions of mRNA and proteins, and that these changes may contribute to Parkinson’s disease. By identifying these altered versions or isoforms, we hope to reveal new ways to detect Parkinson’s earlier and develop treatments that directly target the underlying molecular changes.
Study Design:
We will use advanced sequencing and protein analysis tools to create detailed maps of RNA and protein changes in brain tissue from people with LRRK2 mutations. We will then identify the most strongly altered isoforms and test whether they can serve as markers of Parkinson’s disease in larger datasets and patient samples. Finally, we will use cell models to study how these altered isoforms affect brain cell health. This combined approach will allow us to connect molecular changes to disease mechanisms and identify promising targets for diagnosis and therapy.
Impact on Diagnosis/Treatment of Parkinson’s disease:
This project could identify reliable markers of Parkinson’s disease caused by LRRK2 mutations, which may also apply to other forms of the disease. In addition, testing how specific isoforms harm brain cells could uncover new drug targets, leading to treatments designed to slow or prevent disease progression.
Next Steps for Development:
If successful, biomarkers identified here could be developed into blood tests that recognize the altered isoforms. These tests would then need to be validated for accuracy and safety in patients. Discovered isoforms that damage brain cells could be targeted in future therapeutic programs.