Targeting the cystine/glutamate antiporter for neuroprotection : insights from mouse models of Parkinson's disease

Parkinson’s disease (PD) is an age-related neurodegenerative condition accompanied by disabling motor symptoms. Preventing or delaying the onset of neuronal death in this disorder represents a pending and unmet need. Although various neuroprotective targets have been proposed in pre-clinical studies, none have been validated as yet in patients. A novel therapeutic target recently proposed in PD is system xc-, a membrane cystine/glutamate antiporter. System xc- is induced in pathological conditions and in turn releases high levels of extracellular glutamate, which can become neurotoxic past a certain threshold, triggering ‘excitotoxicity’. In the context of the current thesis, we evaluated system xc- as a possible target for neuroprotection in two toxin-based models with distinct mechanisms of action: the intranigral lactacystin mouse model (proteasome inhibition) and the systemic MPTP mouse model (mitochondrial dysfunction). In the first part of the thesis, we characterized the behavioral, neurochemical, and neurodegenerative changes following lactacystin administration in mice as a model of early stage PD. Subsequently, using mutant mice with a genetic deletion of xCT (the specific subunit of system xc-), we investigated the involvement of system xc- in lactacystin- or MPTP-induced loss of nigral dopamine neurons. Our results indicate that absence of system xc- provides age-related neuroprotective effects against lactacystin administration (observed in aged, but not adult mice), but does not influence the neurodegenerative changes following MPTP administration in adult mice (sensitivity of aged mice not investigated). Our findings confirm the involvement of system xc- in PD-related neurodegenerative changes in the ageing brain and support its further development as neuroprotective target.