Mutations in LRRK2 cause an inherited form of Parkinson's disease (PD), and variations in LRRK2 can increase disease risk, indicating that the protein is key in the entire PD disease population. This proposal is based on our previous findings that dysfunctional LRRK2 regulates vesicular trafficking (movement of storage packets in the cell) events, especially those associated with the proper breakdown of proteins and lipids. Intracellular vesicular trafficking events are regulated by a set of small GTPases called Rab proteins, and LRRK2 may be able to regulate at least some of those Rab proteins. Dysfunctional LRRK2 can cause deficits in vesicular trafficking and protein breakdown. Defects in intracellular trafficking triggered by abnormal Rab protein activity often occur in other parts of the cell as well.
We hypothesize that structural changes in distinct parts of the cell, paralleled by functional deficits, may provide a robust readout for compounds targeting LRRK2 activity in a neuronal as well as non-neuronal context.
We will determine functional and structural alterations in parts of the cell related to the breakdown of vesicular trafficking. For this purpose, we will use cells from individuals with PD who carry LRRK2 mutations and cells from LRRK2 pre-clinical models. The latter types of cells will be grown over long periods of time to mimic aging. In addition, we will attempt to study how LRRK2 may regulate Rab proteins and will test a set of kinase inhibitors to determine whether they can rescue vesicular breakdown.
Impact on Diagnosis/Treatment of Parkinson's Disease:
There is a lack of cellular models available to measure the effects of LRRK2 kinase inhibitors in neuronal cells. Functional and structural changes observed in the presence of dysfunctional LRRK2 may provide a valid readout, possibly in a cell-type-specific manner. In addition, the proposed studies may highlight novel pharmacological targets, including specialized targets in peripheral tissues related to the safety liability issues observed upon kinase inhibition in pre-clinical models.
Next Steps for Development:
Our studies may contribute to the establishment of tests using samples from individuals with PD, enabling determination of target engagement and/or helping in establishing proper dosing regimens.