LRRK2 interacts with over 60 proteins and alters several molecular pathways, including autophagy (cell break down), mitochondria (powerhouses of the cell), neurites (cellular projections) outgrowth and branching and vesicles (storage packets) and membrane (outside layer) and synaptic (site of communications) changes. To successfully identify therapeutics with minimal off-target effects, it is important to understand these molecular changes and their relationships to Parkinson's disease (PD). In this project, we will use SEED, a computer simulation program, to identify therapeutic targets of mutant LRRK2. Promising targets will be validated using pre-clinical models of PD.
We hypothesize that using a computer simulation and pre-clinical models will help us narrow the search for therapeutic targets of LRRK2 function and PD-related markers.
We have built a computer simulation platform, SEED, to analyze pathways within the neuron. Using this platform, we will use existing data to build a LRRK2-specific model, manipulate the expression and function of LRRK2 to both create computer models of PD and reverse the abnormalities observed in these models and validate the results of these findings in pre-clinical models of PD. The results from these experiments can help us narrow in on potential therapeutic targets that are likely to be effective in PD.
Impact on Diagnosis/Treatment of Parkinson's Disease:
Computer simulation may aid in rapid testing and identification of potential disease-modifying therapeutic targets with minimal off-target effects. These findings can be used to develop novel therapies for LRRK2-mediated PD that may also extend to sporadic forms of PD (a type of PD with no known cause).
Next Steps for Development:
Further investigation of LRRK2 targets will increase our understanding of the molecular pathways involved with its malfunction and will guide future efforts to create disease-modifying therapies.