Journal
JOURNAL OF NEUROCHEMISTRY
Volume 133, Issue 4, Pages 558-571Publisher
WILEY-BLACKWELL
DOI: 10.1111/jnc.13071
Keywords
cellular stress; excitatory amino acid transporter; gamma-glutamyl transpeptidase; glutathione; multi-drug resistance protein; prion protein
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Funding
- New Jersey Commission for Spinal Cord Research
- Li Ka-Shing Foundation
- Deutsche Forschungsgemeinschaft [Scha 185/64-1]
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Prion protein (PrP) plays crucial roles in regulating antioxidant systems to improve cell defenses against cellular stress. Here, we show that the interactions of PrP with the excitatory amino acid transporter 3 (EAAT3), gamma-glutamyl transpeptidase (gamma-GT), and multi-drug resistance protein 1 (MRP1) in astrocytes and the interaction between PrP and EAAT3 in neurons regulate the astroglial and neuronal metabolism of the antioxidant glutathione. Ablation of PrP in astrocytes and cerebellar neurons leads to dysregulation of EAAT3-mediated uptake of glutamate and cysteine, which are precursors for the synthesis of glutathione. In PrP-deficient astrocytes, levels of intracellular glutathione are increased, and under oxidative stress, levels of extracellular glutathione are increased, due to (i) increased glutathione release via MRP1 and (ii) reduced activity of the glutathione-degrading enzyme gamma-GT. In PrP-deficient cerebellar neurons, cell death is enhanced under oxidative stress and glutamate excitotoxicity, when compared to wild-type cerebellar neurons. These results indicate a functional interplay of PrP with EAAT3, MRP1 and gamma-GT in astrocytes and of PrP and EAAT3 in neurons, suggesting that these interactions play an important role in the metabolic cross-talk between astrocytes and neurons and in protection of neurons by astrocytes from oxidative and glutamateinduced cytotoxicity.
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