System xc- as a novel therapeutic target to limit neurodegeneration in Parkinson’s disease

Parkinson’s disease (PD) is an age-related neurodegenerative disorder with gradual deterioration of motor function. Current treatment strategies rely on symptomatic drugs to manage the motor symptoms, without interfering with the disease process. Finding a neuroprotective strategy in PD remains, as such, an urgent and unmet need. We have recently identified the cystine/glutamate
antiporter system xc- as a possible target for neuroprotection in animal models of this disorder.
With the current project, we will test this premise in more detail, and evaluate whether genetic deficiency of system xc- is able to protect nigral dopamine neurons of mice against pathogenic pathways highly linked with PD, namely mitochondrial dysfunction. In this target validation study we will employ aged animals, and investigate both male and female mice, in order to increase the translational value of our results.
Next, as a first step towards clinical translation, we aim at reproducing the strongest diseasemodifying effects observed after genetic deletion of system xc-, by pharmacologically inhibiting system xc- with sulfasalazine. By using a multi-model approach and a clinically relevant design, we will provide critical evidence for the potential of system xc- as therapeutic target to limit neurodegeneration in PD.