Prion protein regulates glutathione metabolism and neural glutamate and cysteine uptake via excitatory amino acid transporter 3

Abstract

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), c-glutamyl transpeptidase (c-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 c-GT. In PrPdeficient 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 c-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.

Improvement of neuronal cell survival by astrocyte‐derived exosomes under hypoxic and ischemic conditions depends on prion protein

“…Interestingly, PrP expression in astrocytes is critical for protecting neurons against oxidative stress (Bertuchi et al, ; Lima et al, ). In agreement with these studies, we had shown that astrocyte‐derived PrP is important for the metabolic support of neurons during hypoxic and ischemic episodes (Guitart et al, ; Kleene et al, ). However, it had remained unclear by which mechanisms this support takes place.…”

“…Next, we analyzed the influence of wild‐type and PrP‐deficient astrocytes on the survival of wild‐type cerebellar neurons by exposing co‐cultures of neurons and astrocytes to hypoxia or H 2 O 2 ‐induced oxidative stress. Of note, the astroglial cell culture system used in the present study contains mainly astrocytes and is devoid of neurons, oligodendrocytes and microglia (Guitart et al, ; Wang et al, ). In co‐culture with wild‐type astrocytes, neurons survived better after exposure to H 2 O 2 or hypoxia , when compared with neurons cultured without astrocytes (Fig.…”

Transition of the prion protein from a structured cellular form (PrPC) to the infectious scrapie agent (PrPSc)

“…The only function of PrP C that is well-understood at the molecular level is its role as the physiological ligand of the G protein-coupled receptor, Gpr126. 19 In this review, we provide an overview of the structurefunction relationship of the mammalian prion proteins, its fragments, and the scrapie prions. [9][10][11] The cellular PrP C physiology is associated with maintaining a balance of the divalent metal ions Cu 2+ and Zn 2+ in the central nervous system.…”

Reactivity of 9‐aminoacridine drug quinacrine with glutathione limits its antiprion activity

“…The failure can be then explained by different levels of GSH in neuronal cell cultures and in prion infected brains with increased amount of astrocytes . In particular, astrocytes not only contain higher levels of GSH than neurons, but also release significant amounts of GSH into the extracellular space . A better understanding of the quinacrine antiprion limits can facilitate drug design of in vivo active compounds based on acridine structure.…”

“…[21] In particular, astrocytes not only contain higher levels of GSH than neurons, but also release significant amounts of GSH into the extracellular space. [22] A better understanding of the quinacrine antiprion limits can facilitate drug design of in vivo active compounds based on acridine structure.…”