LRRK2 Phosphatases Confirmation
Research Grant, 2013
This grant builds upon the research from a prior grant:
Promising Outcomes of Original Grant:
The molecular events that precipitate the onset of Parkinsonís disease (PD) have yet to be precisely defined; however current research indicates that the Leucine Rich Repeat Kinase 2 (LRRK2) protein plays a central role in the disease. LRRK2 is a cellular signaling protein, in other words itís a protein involved in fine tuning how cells run by turning cellular processes on and off. LRRK2 itself is subject to this fine tuning and elucidating what flips LRRK2ís on-off switches is crucial to understanding PD pathogenesis and to developing novel PD therapies. In our international collaboration between the KU Leuven (Leuven, Belgium) and The Parkinsonís Institute (Sunnyvale, CA), we have used chemical biology and reverse genetics techniques to identify candidate phosphatases and phosphatase regulators responsible for dephosphorylating LRRK2. Our initial data has confirmed protein phosphatase 1 (PP1) as a LRRK2 phosphatase.
Objectives for Supplemental Investigation: † † † † ††
Here we will study the dynamic regulation of one such on-off switch involving adding (by enzymes called kinases) and removing phosphates (by enzymes called phosphatases) from LRRK2. For instance, several LRRK2 disease mutants display reduced cellular phosphorylation compared to wild type LRRK2. Also, treatment of cells and animals with compounds inhibiting LRRK2 kinase activity leads to dephosphorylation of LRRK2. In this study, we will elucidate the regulation of PP1 and other phosphatases in dephosphorylating LRRK2.
Importance of This Research for the Development of a New PD Therapy: † † †
Understanding LRRK2 phosphoregulation is relevant to potential PD treatments. Indeed, small molecule inhibitors of LRRK2 kinase are in development as potential PD drug therapies. It is therefore crucial to understand the molecular consequences of LRRK2 inhibitor treatment such as the kinase inhibitor induced dephosphorylation of LRRK2. Also, since the LRRK2 phosphatase dynamically regulates LRRK2 in cells, the knowledge we will generate here will open the door to therapeutic targeting of LRRK2 activity via targeting its phosphatases, or the phosphatasesí regulatory proteins.
Signal Transduction and LRRK2 Biology Program Director at The Parkinson's Institute
Location: Sunnyvale, California, United States
Associate Professor at Jean-Pierre Aubert Research Center
Location: Lille, France
Professor at Laboratory for Neurobiology and Gene Therapy, KU Leuven
Location: Leuven, Belgium