Non-kinase Targets in LRRK2 Biology
MJFF Research Grant, 2012
We aim to understand how mutations in one gene, LRRK2, lead to Parkinsonís disease. We will do this by focusing on one region of the protein that has not had much attention and carries a specific risk factor for Parkinsonís in some human populations, G2385R. Our past work suggests this version has some very unusual properties and we think we can use this to understand the protein better and develop new therapeutic approaches.
We think we can predict how the G2385R mutation affects LRRK2 function based on our prior results across several studies, but we need to test these ideas to see if we are right. We will do this in one set of experiments and we will also look at human and mouse proteins to see if they are similar or different. This is important because our second set of experiments will be to see if when we make mice carry a 2385R mutation, we see the effects we predict from our biochemical assays. In the long term, we think this will provide an interesting model of this mutation.
Relevance to Diagnosis/Treatment of Parkinsonís Disease:†††††††††††††††††††††
We hope that we can provide a new way of thinking about LRRK2 that has two outcomes. First, we hope that we will understand whether having too little LRRK2 is risky in the way that too much LRRK2 activity is thought to be. If so this would have an impact on the types of therapies under development by suggesting which are more likely to work. Second, we will include some experiments that, while risky, might give us other ways to inhibit LRRK2 that are not currently being explored.
The first outcome from these experiments will be to understand how G2385R risk factor affects the protein LRRK2. The second is that we will have made a new pre-clinical model that we can use to further develop our understanding of how mutations cause PD.
We found that the G2385R version of lrrk2, which acts as a genetic risk factor for Parkinsonís disease, has lower levels than the normal version of the protein. We spent some time trying to understand why this is, and conclude that the mutant protein is slightly misfolded. What we thought we would find, but didn't, is this would be due to changes within LRRK2 itself, instead we found an increased self interaction, which may be why G2385R causes the disease. We are committed to making a pre-clinical model of the same variant using gene engineering but have, almost by accident, found that human and mouse lrrk2 are not quite the same. We are going to keep working on this problem until we understand how mice and human genes are slightly different.
Senior Investigator at National Institute on Aging, National Institutes of Health
Location: Bethesda, Maryland, United States