Loss of system xc- protects against proteasomal inhibition-induced neurodegeneration in aged mice

Parkinson's disease (PD) is an age-related neurodegenerative disorder in which nigrostriatal dopamine (DA)-ergic neurons are progressively lost. The cause of DA-ergic cell death is incompletely understood but seems to involve activation of pathogenic pathways related to oxidative stress, mitochondrial dysfunction, glutamate excitotoxicity, and neuroinflammation. Furthermore, patients with PD demonstrate impaired proteostasis, as they show decreased proteasomal activity in the substantia nigra, as well as hallmark signs of protein aggregation. Despite important advances in understanding the pathogenesis and clinical profile of PD, therapeutic approaches targeting disease progression remain limited. System xc- is a plasma membrane antiporter that brings cystine inside the cell, and exports glutamate in the extracellular environment. As the imported cystine can be used for GSH synthesis, system xc- is believed to bridge oxidative stress and glutamate excitotoxicity, pathways that co-occur in PD. We have previously demonstrated that nigral DA-ergic neurons of system xc- deficient mice are protected against 6-hydroxydopamine, pointing to this glutamate transporter as a potential new therapeutic target in PD (Massie et al. FASEB J 2011 25(4):1359-1369). Still, promising disease-modifying targets failed to translate so far to the clinic, potentially due to repeated use of animal models with limited mechanisms of toxicity. In order to better understand the validity of system xc- as point of pharmacological intervention, we investigated the reaction of system xc- deficient mice to proteasomal inhibition-induced cell death. Our recent data demonstrate that aged system xc- deficient mice are resistant against lactacystin-induced neurodegeneration, both at the level of the nigral DA-ergic neurons, and at the level of striatal DA content, when compared to age-matched wild-type littermates. Interestingly, however, adult system xc- deficient mice demonstrate similar degrees of nigrostriatal DA-ergic neurodegeneration compared to wild-type littermates, highlighting a complex interplay between ageing, proteasomal dysfunction, and glutamate homeostasis. Our observations therefore support system xc- as a novel therapeutic target for neuroprotection against age-related nigrostriatal DA-ergic neurodegeneration in PD.