C054 - Loss of system xc- protects against proteasomal inhibition-induced neurodegeneration in aged mice

Aim: We recently proposed the cystine-glutamate antiporter system xc-as a potential neuroprotective target in Parkinson’s disease (PD), an age-related neurodegenerative disorder. System xc- is an important source of extrasynaptic glutamate and is enhanced in response to inflammation and oxidative stress, thereby decreasing the threshold for excitotoxicity. Furthermore, it modulates neuroinflammation, by favouring the pro-inflammatory, neurotoxic microglial phenotype. Expression of xCT, the specific subunit of system xc-, is increased in the brain of several models for PD and loss of system xc- (xCT-/- mice) is protective in the 6-OHDA mouse model for PD both in young and aged mice. However, it does not affect the susceptibility for MPTP-induced neurotoxicity in young mice. To further explore system xc- as a novel target to treat PD, we investigated the effect of system xc-- deficiency on proteasome-inhibition induced nigrostriatal degeneration