Transglutaminase 2 Inhibitors as a Disease-Modifying Treatment for Parkinson's Disease

Study Rationale:
Buildup and clumping of protein alpha-synuclein is a hallmark of Parkinson's disease (PD) and a likely cause of neurodegeneration and, ultimately, symptoms. It's important to know what causes the clumping to develop treatments that prevent it and, therefore, slow disease progression. We have shown that one factor that can cause alpha-synuclein clumping and make it more toxic is a protein called transglutaminase 2 (TG2). The goal of this study is to identify compounds that can travel to the brain and deactivate TG2 (inhibitors) and test their efficacy in the laboratory.

Hypothesis:
We hypothesize that TG2 inhibitors in the brain can reduce abnormal alpha-synuclein clumping and prevent or slow brain cell damage.

Study Design:
Potential TG2 inhibitors will be evaluated and the best one will be tested in a pre-clinical model with Parkinson's features. The impact of this treatment on alpha-synuclein's ability to clump and damage the brain will be assessed.

Impact on Diagnosis/Treatment of Parkinson's Disease:
Identifying TG2 inhibitors that prevent or minimize the abnormal clumping of alpha-synuclein can help develop a disease-modifying treatment for PD.

Next Steps for Development:
If the efficacy of a TG2 inhibitor is demonstrated in the pre-clinical model of PD, we will optimize this treatment and develop it further until it is ready for testing in clinical trials.