Rapport final
System xc– as a novel therapeutic target to limit neurodegeneration in Parkinson’s disease - Massie Ann
With this project we aimed at providing further evidence for the therapeutic potential of system xc-inhibition in Parkinson’s disease (PD), using different models in aged mice. The proposed inflammation-induced model did not produce any neurodegeneration in our hands -neither did variants of this model- and could thus not be used to model PD.
We did investigate the susceptibility of aged mice for MPTP-induced nigrostriatal degeneration. System xc--deficiency did, however, not protect aged mice against MPTP-induced toxicity.
Furthermore, we showed that the pharmaceutical strategy that is routinely used to inhibit system xc- in preclinical research -i.e. sulfasalazine treatment- induced undesired side-effects in young-adult mice. These effects were not related to inhibition of system xc as they were equally present in system xc-deficient mice. Still, as aged mice would have difficulties dealing with the observed sickness, we did not use this strategy in aged mice with ongoing neurodegeneration.
Although we have been unable to confirm the therapeutic potential of targeting system xc in PD, we did obtain very interesting data on the involvement of system xc- in aging. We showed that mice with a genetic deletion of xCT, the specific subunit of system xc-, have an increased lifespan and are protected against age-related impairment in hippocampal function and memory. We could link this protection to changes in the hippocampal metabolome that are predictive for improved cognitive function.
Furthermore, we obtained insight in the modulation of cortico-striatal neurotransmission by system xc- and how this affects social behavior of mice.