Targeting Novel Transcriptional Pathways to Reduce Alpha-synuclein Expression

Study Rationale:
Many scientific studies have shown that one of the major causes of Parkinson's disease (PD) is the accumulation of a protein named alpha-synuclein in a certain type of neurons. When these neurons produce high quantities of this protein, they die and their loss triggers a dysfunction of the brain that is responsible for the motor symptoms of PD; however, the reasons for this excessive production of alpha-synuclein are mostly unknown. A better understanding of the molecular mechanisms controlling the synthesis of alpha-synuclein in the brain should help develop novel neuroprotective therapeutic strategies.

Hypothesis:
We have identified three proteins, ZSCAN21, TRIM17 and TRIM41, that could play an important role in the production of alpha-synuclein. TRIM17 may prevent TRIM41 to trigger the destruction of ZSCAN21 which is known to induce the synthesis of alpha-synuclein in the brain.

Study Design:
Our aim is to test whether interfering with these proteins may reduce the amount of alpha-synuclein in neurons, prevent neuronal death and thus halt the disease. For this purpose, we will artificially prevent the production of TRIM17 and ZSCAN21 in cells that can be transformed into neurons in petri dishes and in pre-clinical models. Then, we will examine whether this manipulation can reduce levels of alpha-synuclein and protect neurons from the toxicity of a drug that induces PD in humans and in pre-clinical models (MPP+/MPTP). In parallel, we will study how these three proteins interact in vitro to test whether disrupting these interactions can reduce the production of alpha-synuclein in human cells.

Impact on Diagnosis/Treatment of Parkinson's disease:
If successful, our study will provide proof-of-concept data that targeting the TRIM17/TRIM41/ZSCAN21 pathway could be used to protect neurons and stop PD progression. Our data should also serve as a base for novel drug design.

Next Steps for Development:
The next steps toward clinical application would include screening of small molecules for their ability to disrupt the interaction between TRIM17, TRIM41 and ZSCAN21 and to protect neurons from MPP+. The most efficient molecules would be tested in the MPTP pre-clinical model of PD and then evaluated in clinical trials as neuroprotective drugs.