title: Dopaminergic neurons of system x(c)⁻-deficient mice are highly protected against 6-hydroxydopamine-induced toxicity.
abstract: Malfunctioning of system x(c)(-), responsible for exchanging intracellular glutamate for extracellular cystine, can cause oxidative stress and excitotoxicity, both important phenomena in the pathogenesis of Parkinson's disease (PD). We used mice lacking xCT (xCT(-/-) mice), the specific subunit of system x(c)(-), to investigate the involvement of this antiporter in PD. Although cystine that is imported via system x(c)(-) is reduced to cysteine, the rate-limiting substrate in the synthesis of glutathione, deletion of xCT did not result in decreased glutathione levels in striatum. Accordingly, no signs of increased oxidative stress could be observed in striatum or substantia nigra of xCT(-/-) mice. In sharp contrast to expectations, xCT(-/-) mice were less susceptible to 6-hydroxydopamine (6-OHDA)-induced neurodegeneration in the substantia nigra pars compacta compared to their age-matched wild-type littermates. This reduced sensitivity to a PD-inducing toxin might be related to the decrease of 70% in striatal extracellular glutamate levels that was observed in mice lacking xCT. The current data point toward system x(c)(-) as a possible target for the development of new pharmacotherapies for the treatment of PD and emphasize the need to continue the search for specific ligands for system x(c)(-).
authors.affiliation: Department of Pharmaceutical Chemistry and Drug Analysis, Research Group Experimental Pharmacology, Vrije Universiteit Brussel, Brussels, Belgium. amassie@vub.ac.be
authors.forename: Ann
authors.initials: A
authors.lastname: Massie
authors.forename: Anneleen
authors.initials: A
authors.lastname: Schallier
authors.forename: Seong Woong
authors.initials: SW
authors.lastname: Kim
authors.forename: Ruani
authors.initials: R
authors.lastname: Fernando
authors.forename: Sho
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Heike
authors.initials: H
authors.lastname: Beck
authors.forename: Dimitri
authors.initials: D
authors.lastname: De Bundel
authors.forename: Katia
authors.initials: K
authors.lastname: Vermoesen
authors.forename: Shiro
authors.initials: S
authors.lastname: Bannai
authors.forename: Ilse
authors.initials: I
authors.lastname: Smolders
authors.forename: Marcus
authors.initials: M
authors.lastname: Conrad
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Plesnila
authors.forename: Hideyo
authors.initials: H
authors.lastname: Sato
authors.forename: Yvette
authors.initials: Y
authors.lastname: Michotte
mesh_terms: D000375:Aging / Q000502:physiology; D027182:Amino Acid Transport System y+ / Q000172:deficiency* / Q000502:physiology; D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism; D003553:Cystine / Q000378:metabolism; D004298:Dopamine / Q000502:physiology*; D005910:Glioma / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D019636:Neurodegenerative Diseases / Q000517:prevention & control; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D016627:Oxidopamine / Q000633:toxicity*; D013378:Substantia Nigra / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D027182:Amino Acid Transport System y+; C492255:Slc7a11 protein, mouse; D018698:Glutamic Acid; D003553:Cystine; D016627:Oxidopamine; D005978:Glutathione; D004298:Dopamine