Validation of a Protein, Transglutaminase 2, as a Way to Reduce Alpha-synuclein Clumping and Toxicity in Parkinson's Disease

Study Rationale:

Accumulation of abnormal aggregates (clumps) of the protein alpha-synuclein is a key feature of Parkinson's disease (PD) and plays a role in neuron degeneration (cell loss). 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 shown that a protein called transglutaminase 2 (TG2) can cause alpha-synuclein aggregation and exacerbate its toxicity. Considering that TG2 has several other functions, the goal of this project is to advance our current knowledge about how exactly TG2 worsens alpha-synuclein clumping and neuron degeneration (break down).

Hypothesis:

We hypothesize that TG2 can link alpha-synuclein molecules together and is responsible for the formation of abnormal clumps and neuron damage.

Study Design:

This hypothesis will be tested in pre-clinical models of PD. The impact of TG2 gene on the tendency of alpha-synuclein to clump and cause abnormalities will also be studied.

Impact on Diagnosis/Treatment of Parkinson's disease:

Gaining a clear understanding about the mechanism through which TG2 promotes alpha-synuclein aggregation and exacerbates neurodegeneration will advance TG2 as a therapeutic target in PD.

Next Steps for Development:

If this study confirms the mechanism of TG2-mediated alpha-synuclein clumping, specific agents that block this process will be tested first in pre-clinical models of PD and subsequently developed for clinical trial testing.