Developing an Inhibitor of Transglutaminase 2 as a Disease-modifying Treatment for Parkinson’s Disease

Study Rationale: Clumping of alpha-synuclein in the brain is a key pathological feature of Parkinson’s disease (PD) and is believed to lead to brain cell degeneration. Identifying factors that initiate or promote this aggregation is critical to develop therapies that reduce or prevent the formation of clumps and, therefore, slow disease progression. We have found that transglutaminase 2 (TG2) is one such factor. We have also identified a drug-like compound that blocks TG2 and prevents alpha-synuclein aggregation. The goal of this project is to test the neuroprotective ability of this compound in a preclinical mouse model of PD.

Hypothesis: We hypothesize that the TG2 inhibitor can reduce the formation of abnormal alpha-synuclein clumps and prevent or slow the degeneration of brain cells.

Study Design: The TG2 inhibitor will be administered in the diet, and its effect in ameliorating the behavioral and brain pathological abnormalities seen in the preclinical PD model will be examined.

Impact on Diagnosis/Treatment of Parkinson’s disease: Demonstrating that the TG2 inhibitor prevents or minimizes the pathological clumping of alpha-synuclein and protects the brain in a preclinical model can lead to the development of a disease-modifying treatment for PD.

Next Steps for Development: If the efficacy of the TG2 inhibitor is demonstrated in the preclinical model of PD, we will optimize this treatment and develop it towards testing in clinical trials.