Pharmacological Targeting of Inflammasome Activation Mechanisms in Synuclein Models of Parkinson's Disease

Promising Outcomes of Original Grant:
Our previous studies confirmed the activation of an immune system complex called the inflammasome is involved in chronic inflammation and the death of brain cells in Parkinson's disease. Under the previous grant, we also identified and confirmed a new signaling pathway involving toxic forms of the protein alpha-synuclein that activates the inflammasome. We demonstrated that this pathway is activated in people with Parkinson's and pre-clinical models of the disease. Crucially, blocking this pathway using a repurposed drug was beneficial in pre-clinical models.

Objectives for Supplemental Investigation:
As the next step in our validation plan, we will evaluate a set of more effective and targeted drugs to block activation of the inflammasome complex in pre-clinical models of Parkinson's disease. This will enable us to extend our previous work in pre-clinical models and isolated immune cells. These studies will assess a promising new therapeutic approach to slow or halt disease progression by blocking persistent activation of the immune system and chronic brain inflammation.

Importance of This Research for the Development of a New PD Therapy:
This project will evaluate a new strategy to inhibit the inflammasome complex and associated brain pathology in Parkinson's disease. We will utilize both repurposed drugs developed for other conditions, as well as new drugs that are currently in development. If our approach is effective, it will confirm a previously unknown role for this pathway in Parkinson's disease and provide the basis for future clinical trials with this class of drugs as new treatments for Parkinson's.