Aged xCT-Deficient Mice Are Less Susceptible for Lactacystin-, but Not 1-Methyl-4-Phenyl-1,2,3,6- Tetrahydropyridine-, Induced Degeneration of the Nigrostriatal Pathway.

Eduard Bentea,Ann Massie,Giulia Albertini,Lila C Winfrey,Laura De Pauw,Hideyo Sato,Cynthia Moore,Lise Verbruggen,Ann Van Eeckhaut,Lauren Deneyer,Charles K Meshul

doi:10.3389/fncel.2021.796635

Abstract

The astrocytic cystine/glutamate antiporter system xc– (with xCT as the specific subunit) imports cystine in exchange for glutamate and has been shown to interact with multiple pathways in the brain that are dysregulated in age-related neurological disorders, including glutamate homeostasis, redox balance, and neuroinflammation. In the current study, we investigated the effect of genetic xCT deletion on lactacystin (LAC)- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced degeneration of the nigrostriatal pathway, as models for Parkinson’s disease (PD). Dopaminergic neurons of adult xCT knock-out mice (xCT–/–) demonstrated an equal susceptibility to intranigral injection of the proteasome inhibitor LAC, as their wild-type (xCT+/+) littermates. Contrary to adult mice, aged xCT–/– mice showed a significant decrease in LAC-induced degeneration of nigral dopaminergic neurons, depletion of striatal dopamine (DA) and neuroinflammatory reaction, compared to age-matched xCT+/+ littermates. Given this age-related protection, we further investigated the sensitivity of aged xCT–/– mice to chronic and progressive MPTP treatment. However, in accordance with our previous observations in adult mice (Bentea et al., 2015a), xCT deletion did not confer protection against MPTP-induced nigrostriatal degeneration in aged mice. We observed an increased loss of nigral dopaminergic neurons, but equal striatal DA denervation, in MPTP-treated aged xCT–/– mice when compared to age-matched xCT+/+ littermates. To conclude, we reveal age-related protection against proteasome inhibition-induced nigrostriatal degeneration in xCT–/– mice, while xCT deletion failed to protect nigral dopaminergic neurons of aged mice against MPTP-induced toxicity. Our findings thereby provide new insights into the role of system xc– in mechanisms of dopaminergic cell loss and its interaction with aging.

Highlights

The cystine/glutamate antiporter system xc− is an astrocytic plasma membrane antiporter (Ottestad-Hansen et al, 2018) that couples the export of glutamate to the import of cystine in an equimolar ratio (Sato et al, 2005)
To evaluate whether genetic deletion of xCT influences proteasome inhibition-induced nigrostriatal degeneration in adult mice, 3–4 months old xCT−/− and xCT+/+ littermates were stereotaxically injected with LAC in the left SNc
Behavioral evaluation of the adult mice revealed a LACinduced acute loss of motor function as assessed using the rotarod test, that could be observed already at 1 week post-surgery in both genotypes [lesion factor: F(1, 40) = 9.74, p = 0.003], and did not progress until 3 weeks post-surgery [lesion factor: F(1, 40) = 8.38, p = 0.006] (Figure 1A). This acute and nonprogressive time-course of LAC-induced behavioral deficit is in line with previous reported data (Bentea et al, 2015b), and indicates an acute effect of the toxin on nigral dopaminergic neurons

Summary

Introduction

The cystine/glutamate antiporter system xc− is an astrocytic plasma membrane antiporter (Ottestad-Hansen et al, 2018) that couples the export of glutamate to the import of cystine in an equimolar ratio (Sato et al, 2005). In addition to its role in regulating redox function, system xc− provides up to 70% of the extracellular glutamate levels in areas of the brain such as the hippocampus (De Bundel et al, 2011) and striatum (Massie et al, 2011). Excessive extrasynaptic glutamate levels can be toxic via overstimulation of ionotropic glutamate receptors (Hardingham and Bading, 2010), a pathway of neuronal stress and toxicity -i.e., excitotoxicity- involved in various neurodegenerative disorders including Parkinson’s disease (PD) (Ambrosi et al, 2014)

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Conclusion