Computer Simulation of LRRK2 and GBA Interactions to Identify Therapeutic Targets for Parkinson's Disease

Promising Outcomes of Original Grant:
Our original project aimed to create a computer simulation of biological pathways involved in Parkinson's disease and how genetic mutations in LRRK2 can change that system so that we could find new targets for therapeutic intervention. We were happy to see strong correlation between the simulation and laboratory results validating that this tool can be used for predictive experiments. We also were able to show that increasing levels of certain chaperone proteins can restore system balance disturbed by the LRRK2 mutation.

Objectives for Supplemental Investigation:
In parallel to the original funded project, the NeuroInitiative team built initial models of another genetic risk factor for Parkinson's, GBA. This supplemental investigation aims to combine these models so that we can explore convergence of two pathways that are generally thought to be unrelated but which both lead to similar Parkinson's disease diagnosis. In this combined model we will test whether inhibition of LRRK2 or activation of GBA might be protective for patients with the other mutation, and also whether these therapies might work for idiopathic (cause unknown) Parkinson's disease where there is no clear genetic contributor. As an exciting step forward over the original project, this supplemental investigation will use human-derived neurons for laboratory validation, which more closely matches our simulations, which are built on human data.

Importance of This Research for the Development of a New PD Therapy:
With the simulation system we can measure changes in every part of the cell as mutations or treatments take effect, which isn't possible in the lab or clinic. With this tool we hope to find new markers of disease and treatment that can be used to accelerate research.