This grant builds upon the research from a prior grant: Structure Window into LRRK2: Kinase or Pseudokinase?
Study Rationale:
Mutations in the LRRK2 gene are a leading genetic cause of Parkinson's disease (PD) and cause dysfunction in the LRRK2 protein. We are studying the structures of normal and abnormal LRRK2. Using electron cryomicroscopy (cryo-EM) -- a technique based on freezing the samples before looking at them under a very powerful microscope -- we can determine the detailed structure of a pure protein extracted from the cell. To study LRRK2 inside the cell, we use another technique, electron cryotomography (cryo-ET), which allows us to characterize LRRK2 attached to microtubules (cell structure supports). We study LRRK2 attached to microtubules because in Parkinson's, the interaction between LRRK2 and microtubules is different and can have a damaging effect on cells.
Hypothesis:
We are using cryo-EM and cryo-ET techniques to advance our understanding of the function and properties of LRRK2 in the cell.
Study Design:
First, we are determining high-resolution structure of LRRK2 using cryo-EM. We also are determining the structure of abnormal LRRK2 attached to microtubules in the cell using cryo-ET. Next, we will confirm and characterize all LRRK2 structures with experimental techniques and investigate how LRRK2 functions and changes within the cell by creating and studying artificial LRRK2 forms.
Impact on Diagnosis/Treatment of Parkinson's Disease:
Understanding LRRK2 structures lays the foundation for designing therapies targeting LRRK2. In addition, this study will help understand how LRRK2 changes its shape and function in the cell, which can suggest ways to target these changes to treat Parkinson's disease.
Next Steps for Development:
In the future, we aim to determine high-resolution structures of LRRK2 to explain how abnormal LRRK2 causes the disease. These structures will enable researchers studying Parkinson's to design novel drugs to slow or stop disease progression.