Objective/Rationale:
Therapeutic strategies targeting aberrant LRRK2 activity hold great promise for the treatment of familial LRRK2 mutant and perhaps idiopathic PD. Development of pharmacodynamic biomarkers of LRRK2 activity is critical to assess therapeutic strategies. The absence of an understanding of LRRK2 regulated signaling and pathogenic pathways pose a challenge to this endeavor. We propose to use an integrated approach to develop LRRK2 therapeutic blood test biomarkers based on the LRRK2 signaling network using established LRRK2 pre-clinical models and human LRRK2 PD patients.
Project Description:
Emerging evidence has linked the aberrant LRRK2 kinase/GTPase activity to PD pathogenesis. However, available experimental tools are limited and prevent the understanding of LRRK2-mediated signaling and pathogenic pathways in the brain that would predict dynamic biomarkers. To address the emerging needs of developing dynamic, efficient, and reliable biomarkers for the assessment of LRRK2 PD therapeutic strategies, we plan to (1) identify signaling fingerprints for the LRRK2 kinase and perturbation of the signaling network caused by G2019S mutation in blood lymphocytes, (2) investigate the relationship of LRRK2 kinase activity to aberrant signaling, and (3) evaluate available kinase inhibitors in reversing the phenotype caused by LRRK2-G2019S. This can help identify the function of LRRK2 and predict efficacy of compounds targeting LRRK2 kinase activity in animal models/human trials and may also predict penetrance.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Our study is designed to predict pharmacodynamic biomarkers of LRRK2 activity that is critical for validating the action of small chemical compounds targeting LRRK2 kinase activity. Our study will not only provide valuable information for pre-clinical development of potent compounds in pre-clinical models, but also establish a platform for understanding the mechanism of drug action in clinical trials due to the easy access of human blood.
Anticipated Outcome:
Our study is expected to provide insight into signaling transduction of LRRK2 kinase and pathogenic pathways of PD mutation in lymphocytes. It may also elucidate related pathways in the CNS that are associated with inflammatory signaling, particularly in glial cells and known to contribute to disease progression in PD. In addition, our study of LRRK2 aSymptoms & Side Effects and Symptoms & Side Effects patients may provide insight into the variable penetrance of LRRK2 mutation.