Study Rationale:
Parkinson’s disease develops in part because brain cells lose the ability to clear away damaged proteins and cell parts, leading to stress and cell death. A gene called LRRK2, which is one of the most common genetic causes of Parkinson’s, makes this problem worse by blocking the cell’s normal recycling systems (lysosomes and autophagy). My recent work has identified another protein, called Rubicon, which naturally acts as a “brake” on these recycling systems and is especially active in neurons. By studying Rubicon, I will uncover new ways by which cells with abnormal LRRK2 can regulate their waste clearance and survival.
Hypothesis:
I hypothesize that reducing Rubicon will improve the recycling ability of neurons carrying Parkinson’s-linked LRRK2 mutations, restoring balance to the cell’s waste-clearance pathways and protecting neurons from damage.
Study Design:
I will use human stem cell–derived neurons carrying Parkinson’s-related LRRK2 mutations and compare them to healthy neurons. By reducing Rubicon levels using modern genetic tools, I will measure how well cells can recycle damaged proteins, clear toxic waste products, and maintain healthy lysosomes. I will also identify the molecular partners that allow Rubicon to block these recycling systems. These studies will help explain how Rubicon contributes to Parkinson’s disease processes and whether relieving its effects can protect vulnerable brain cells.
Impact on Diagnosis/Treatment of Parkinson’s disease:
If successful, this work will highlight Rubicon as a new potential target for therapy, offering an approach that boosts the cell’s natural cleaning systems rather than focusing only on blocking LRRK2. This could open new directions for preventing or slowing Parkinson’s disease progression.
Next Steps for Development:
Future steps will include testing Rubicon-targeting strategies, such as gene-based therapies or small molecules, in preclinical Parkinson’s models. These studies will promote development of approaches that combine LRRK2 inhibition with Rubicon modulation to improve treatment outcomes and protect neurons over the long term.