Funded Studies
Study Rationale: The aggregation of alpha-synuclein and tau converts these proteins from a biologically functional state into toxic, fibrous deposits in the brains of people with Parkinson’s disease (PD) and Alzheimer’s disease (AD). These proteins also interact with each other, inducing and accelerating their aggregation. The accumulation of these protein aggregates is believed to be the main cause of the onset and progression of PD and AD. In this study, we will assess whether small molecules “chaperones” that stabilize the biologically functional form of tau will prevent its aggregation, an effect that should slow the progression of disease.
Hypothesis: We hypothesize that by stabilizing the functional form of tau and decreasing its affinity for alpha-synuclein, our small molecule chaperones will prevent the aggregation of tau—even in the presence of alpha-synuclein aggregates.
Study Design: We will test our novel tau pharmacological chaperones for their ability to prevent aggregation of tau proteins when “seeded” by either alpha-synuclein fibrils or tau fibrils derived from a post mortem AD brain. We will conduct these studies on tau proteins in a test tube, in cells, and in a mouse model of tau aggregation. Ultimately, we seek to develop an active compound that can reduce seeded aggregation of tau, prevent cell toxicity due to tau aggregation and show a significant therapeutic effect in a mouse model of tau aggregation.
Impact on Diagnosis/Treatment of Parkinson’s disease: Our project could lead to the development of a novel, small-molecule inhibitor of tau aggregation that has reduces tau aggregation and has therapeutic value in both disease-modifying and preventive contexts for PD and AD.
Next Steps for Development:
Our small-molecule tau aggregation inhibitor could be moved into preclinical studies to determine its safety and toxicity profile with a goal to take it into clinical trials for the treatment of PD and AD.