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Funded Studies

Kinase Activity-mediated Changes in LRRK2-Parkinson's and Sporadic Parkinson's Cells and Rab Protein Function

Promising Outcomes of Original Grant:
Our previous studies have demonstrated deficits in cohesion, positioning, and polarity (important characteristics of cells that help regulate function) in different cell types expressing a dysfunctional form of the protein LRRK2. These alterations were associated with abnormal accumulation of a recently identified LRRK2 kinase substrate (location on protein where reactions occur) within the cell. These alterations were also found in skin cells derived from those with Parkinson's disease (PD) caused by LRRK2 mutations (LRRK2-PD) as compared to healthy participants, and, in all cases, were reversed by distinct LRRK2 kinase inhibitors.

Objectives for Supplemental Investigation:
Given the data obtained under the original funded project, we aim to determine whether our findings can also be observed in easily-obtainable cells from those with LRRK2-PD. Alterations in key cellular processes will be correlated with changes in the localization and/or phosphorylation (modification) of a subset of LRRK2 kinase substrates, and the effect of LRRK2 kinase inhibitors on those readouts will be determined.

Importance of This Research for the Development of a New PD Therapy:
While highly specific LRRK2 kinase inhibitors have been developed and LRRK2 kinase substrates have been identified, determining the efficacy of kinase inhibitors in future clinical trials is likely to benefit from cell biological assays (tests) in easily-obtainable cells from those with PD.


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