Objective/Rationale:
LRRK2 is one of the most important genetic risk factors that we know about for Parkinson’s disease: Tens of thousands of people in the US have mutations in this gene that could lead to them developing the disease. Although we know that these mutations can cause Parkinson’s, we don’t know much about what LRRK2 does in the brain and exactly how it leads to brain cells dying. The aim of this project is to find out how the levels of LRRK2 vary in the different parts of the brain and to find out whether there are different sized forms of LRRK2 (called isoforms) in different areas of the brain.
Project Description:
We are going to use several approaches to find out what LRRK2 looks like in the brain. First of all, we are going to extract the RNA templates that code for LRRK2 from different regions of the brain and examine these templates. We also want to look directly at the LRRK2 protein that is produced from the RNA, and so we will extract protein from these brain regions and analyze this using mass spectrometry, which allows you to establish how big a protein is. Combining information from these two approaches will let us generate a picture of LRRK2 expression, both in terms of level and different isoforms, across the brain.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Knowing more about how much LRRK2 there is in different areas of the brain, and whether there are different isoforms, will give us a valuable insight into what LRRK2 is doing in the brain. This, in turn, will be important in helping to understand how LRRK2 is going wrong in Parkinson’s disease and how we can target LRRK2 to try and develop treatments.
Anticipated Outcome:
At the end of this project, we will have a map of what LRRK2 looks like in a number of regions of the brain. We, and other laboratories, can then use this information to learn more about LRRK2.
Final Outcome
The aim of this project was to look at whether there are different versions of a gene called Leucine Rich Repeat Kinase 2 (LRRK2) in the human brain. We know that LRRK2 is very important for Parkinson’s disease, as some people have changes, called mutations, in the gene that can cause them to develop Parkinson’s – so the more we know about how LRRK2 works and what it does in the brain the better. We found that there are several different versions (called “splice isoforms”) in different parts of the human brain. What was really interesting is that we looked in the part of the brain that suffers the most damage in Parkinson’s, called the substantia nigra, and the LRRK2 we found there could exist in several versions – some of which were not present in other regions of the brain that we looked at. This is potentially very important, as these different versions might not react in the same way to drugs that are being developed to target LRRK2. We are now working to find out more about why there are different forms of LRRK2 in the brain, what they might be doing and how they are involved in the steps that lead to Parkinson’s disease.