Promising Outcomes of Original Grant:
Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) account for up to 13% of familial Parkinson's disease (PD) patients. One widely held hypothesis has been that LRRK2 levels or kinase activity regulates neurite growth, but our data show that pre-clinical model neurons expressing increased levels of LRRK2 or expressing LRRK-G2019S have axons and dendrites that are similar in length and branching patterns to non-transgenic controls.
Objectives for Supplemental Investigation:
There may be changes in dynamic aspects of axon or dendrite outgrowth or differences in growth over a longer time course that were not detected. Since our findings run counter to what has become a prevailing viewpoint, we propose to address these possibilities directly. Additionally, our preliminary data show that LRRK2 levels and kinase activity alter the course of synaptogenesis. This would be expected to affect the function of neural circuits. In view of the relationship between LRRK2 mutations and PD, such changes may impart vulnerability. We propose to test the hypothesis that LRRK2 regulates synaptogenesis and in so doing we hope to identify clear and reproducible LRRK2 biological targets.
Importance of This Research for the Development of a New PD Therapy:
The identification of biological actions driven by LRRK2 activity will provide a system in which we can test the actions of potential therapeutic agents targeting LRRK2.