Loss of system xc- protects against proteasomal inhibition-induced neurodegeneration in aged mice
Lise Verbruggen1, Eduard Bentea1, Lauren Deneyer1, Giulia Albertini1, Hideyo Sato², Ann Massie1
1Center for Neurosciences, Vrije Universiteit Brussel, Brussels, Belgium
2Department of Medical Technology, Niigata University, Japan

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.
Method: Young (3-4 months) and aged (20-24 months) xCT+/+ and xCT-/- mice were intranigrally injected with the proteasome inhibitor lactacystin. Three weeks after injection, nigrostriatal degeneration (TH immunohistochemistry and striatal dopamine content) and neuroinflammation (Iba-1 immunohistochemistry) were studied.
Results: Our data demonstrate that aged, but not young, xCT-/- mice are significantly protected against lactacystin-induced nigrostriatal degeneration, when compared to age-matched wildtype littermates. These data suggest an involvement of system xc- in the interplay between ageing, proteasomal dysfunction, neuroinflammation and neurodegeneration, and highlight the importance of using aged mice to investigate an age-related disorder.
Conclusion: Our observations support system xc- as a novel therapeutic target for protection against nigrostriatal degeneration in PD.

Original languageEnglish
Publication statusPublished - 2018
Event11th FENS Forum of Neuroscience - Berlin, Germany
Duration: 7 Jul 201811 Jul 2018

Conference

Conference11th FENS Forum of Neuroscience
CountryGermany
CityBerlin
Period7/07/1811/07/18

ID: 45389605