Although leucine-rich repeat kinase 2 (LRRK2) is the greatest known genetic contributor to Parkinson's disease (PD), little is known about its structure and function. To better understand how this important protein functions in healthy and PD-affected brain cells, we will study the structures of normal and abnormal LRRK2, that is, LRRK2 from cells with genetic changes -- mutations -- in the LRRK2 gene.
Knowing LRRK2 structures will help us understand its function in health and disease. Also, we hypothesize that microtubules -- cell structure supports -- coated with LRRK2 may represent a sign of disease in cells of PD patients.
When LRRK2 is not performing its function, one part of the protein -- the inhibitory fragment -- reaches over and covers another part, making the protein inactive. By removing the inhibitory fragment, we created a stable and active molecule that can still attach to microtubules inside the cell. Using several sophisticated research techniques, our interdisciplinary team will determine the structure and function of this active fragment at low and high resolutions inside and outside the cell. We will also analyze samples from people with PD and from pre-clinical models with LRRK2-coated microtubules.
Impact on Diagnosis/Treatment of Parkinson's disease:
A thorough understanding of LRRK2 will allow us to design new therapeutic strategies.
Next Steps for Development:
All LRRK2 structures discovered in the course of this study will be shared with the research community as the study progresses to enable their use in drug discovery.