Promising Outcomes of Original Grant:
The goal of our original study was to determine the best conditions for collecting and processing blood cells intended for testing the function of LRRK2, a protein that plays an important role in inherited Parkinson's disease (PD). We developed three sensitive tests that can measure the amount of LRRK2 present in a biosample, if the protein has any specific features that affect its function, and how well it functions (i.e., how active it is). We tested blood cells donated by people who carry a mutation (change) in the LRRK2 gene and discovered that in their cells protein LRRK2 is present in the same amount but is more active.
Objectives for Supplemental Investigation:
As we continue this study, we aim to replace one of the reagents in our test with a new reagent called nanobodies to see if that will allow us to measure other important characteristics of the protein. One of the characteristics we aim to test is the presence of LRRK2 dimers (two LRRK2 molecules stuck together). Unique properties of nanobodies, including their very small size and capability to react with other molecules in a way that depends on their shape, makes nanobodies powerful tools for detecting LRRK2 dimers.
In cases of PD where there is no mutation in the LRRK2 gene, there is strong evidence that the protein is also more active; therefore, tests that can measure changes in its shape may be the best way to follow this important protein during the disease progression.
Importance of This Research for the Development of a New PD Therapy:
Because LRRK2 may be involved in many forms of PD, not only the inherited ones caused by a mutation, we critically need tools that can measure many different kinds of changes in LRRK2, including its activity, shape and the presence of dimers. We will include these new tools in our existing tests and study their performance. We expect this to help identify people with Parkinson's who may benefit from treatments that target LRRK2 activity and also to provide a way to test whether these new drugs indeed make LRRK2 less active.