Exploiting Ser910/935 Phosphorylation and 14-3-3 Binding to Develop Biomarkers for LRRK2 Activity
Pharmacodynamic Biomarkers of LRRK2 Activity, 2010
There is great excitement that drugs that target an enzyme termed LRRK2 may have utility for the treatment of Parkinson’s disease. Many companies are attempting to develop LRRK2 inhibitors, but there is currently no robust technology to test the effectiveness of drugs being developed in cell or pre-clinical models. Our objective is to build upon recent breakthrough that our laboratory has made which has lead to the identification of a downstream biological process controlled by LRRK2. We wish to exploit these findings by developing robust methodology and reagents that will help establish the effectiveness of drugs that target LRRlllllK2 for the treatment of Parkinson’s disease.
We have discovered that LRRK2 enzyme switches on a pathway that regulates a form of modification on LRRK2 termed “phosphorylation”. Importantly, we have demonstrated that phosphorylation of LRRK2 can be used to monitor the effectiveness of LRRK2 inhibitors. With the support of MJFF we wish to generate the state of the art monoclonal antibodies to detect phosphorylation of LRRK2 in cells as well as blood samples derived from pre-clinical models or humans administered an LRRK2 inhibitor. The aim is to generate a simple, sensitive and robust methodology to monitor LRRK2 phosphorylation. Our mission is to make these reagents and methods available to any company or research groups wising to develop and test LRRK2 inhibitors.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
We hope that the tools and assays we generate will be useful to researchers as well as pharmaceutical companies developing and evaluating LRRK2 inhibitors for the treatment of Parkinson’s disease. We anticipate that this research will accelerate preclinical as well as clinical evaluation of LRRK2 inhibitors. Overall this could aid and speed up the development of a new treatment for Parkinson’s disease
We aim to produce state of the art reagents and elaborate technologies that will help characterization and development of LRRK2 inhibitors for the treatment of Parkinson’s disease. These tools and methods will greatly facilitate the ability of researchers and pharmaceutical companies to work out more quickly what drugs are the most effective at targeting the LRRK2 enzyme.
Director of the MRC Protein Phosphorylation and Ubiquitylation Unit at MRC Protein Phosphorylation Unit, University of Dundee
Location: Dundee City, United Kingdom