Study Rationale:
Parkinson’s disease (PD) is caused by degeneration of dopamine neurons. Neurons are constituted by a cell body and projections called axons by which neurons communicate. Previous studies have shown that degeneration of neurons in PD starts in the axons, which makes them an attractive therapeutic target. In our lab, we have evidence that axons degenerate by a mechanism called necroptosis.
Hypothesis:
In this project, we will study whether inhibiting necroptosis can prevent axonal degeneration, neuron death and therefore PD progression in disease models.
Study Design:
To carry out this project we will induce PD in pre-clinical models. To investigate the involvement of necroptosis in the development of the disease, we will target this death mechanism using two different methods, a pharmacological one and a genetic one. For the first method, we will treat models with a drug that inhibits necroptosis. For the second method, we will use genetically modified models that cannot undergo necroptosis. In both cases, we will test whether blocking necroptosis can inhibit PD progression.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
Existing treatments for PD can only decrease symptoms, but there are no therapies available that can stop the progression of the disease. If necroptosis is involved in the early stages of the disease, where axons start to degenerate, this study will provide a novel and druggable target for therapeutic intervention.
Next Steps for Development:
If successful, the efforts would have to be directed toward the design of an anti-necroptotic drug for further clinical use. For this, we will initiate a collaborative work with a pharmaceutical company in order to perform a drug screening or to design and develop a new anti-necroptosis molecule.