This grant builds upon the research from a prior grant: Investigating signaling pathway dysfunction linked to LRRK2
Promising Outcomes of Original Grant:
Our project investigated whether LRRK2 had an impact on a particular signaling system in the cell called the mTOR pathway. This pathway helps to control how cells respond to starvation, and has been linked to a number of neurodegenerative diseases before (including Parkinson’s disease). To start with we looked at two proteins in the mTOR pathway that control how quickly cells make new protein, 4EBP and S6, however we didn't see any alterations in these when we manipulated LRRK2. We did see differences when we looked at autophagy, a process downstream of mTOR that helps cells recycle the basic building blocks of the cell.
Objectives for Supplemental Investigation:
Based on our previous study funded by the MJFF highlighting a role for LRRK2 in controlling autophagy, we now want to focus on this process and find out exactly how and where LRRK2 acts on it. We are using a number of tools to examine this, including pre-clinical cells that have had LRRK2 genetically removed, skin cells from Parkinson’s patients who have mutations in LRRK2 and a compound that specifically targets LRRK2. By combining these with a number of drugs that can stimulate or inhibit individual steps in the initiation and progress of autophagy we hope to generate a clear picture of what LRRK2 is doing.
Importance of This Research for the Development of a New PD Therapy:
If we can confirm that LRRK2 acts to influence autophagy, and find out what mutations in LRRK2 do to this process, we will have made an important advance in our understanding of how mutations in LRRK2 cause Parkinson’s disease. Importantly, this will open a new therapeutic avenue for investigation.
Final Outcome
Our project was focused on investigating what LRRK2 mutations do to a process called autophagy (pronounced ort-oh-fay-gee). Autophagy is one of the ways in which cells get rid of waste: it literally means “self eating”, and is often used by cells when they are starved of nutrients. Some of our previous research had revealed that LRRK2 was involved in autophagy, and we wanted to find out exactly how. We found that if you use a drug to turn LRRK2 off, you get a switching on of autophagy. Lots of research suggests that some of the mutations in LRRK2 make it hyperactive, and so we looked in skin cells from patients who had mutations in LRRK2 to see if there were any changes in autophagy. What we discovered was that those skin cells that came from people with a LRRK2 mutation were different from healthy controls in the way that they used autophagy to respond to starvation. We’ve also looked at autophagy in brain samples from people with LRRK2 mutations, where we see differences from what is seen in normal human brains and parkinson’s disease brains from people who didn't have a mutation. All of this points to LRRK2 having an important role in controlling autophagy, and we are continuing to investigate this.