Vanishing white matter disease (VWMD) is an inherited autosomal-recessive hypomyelinating disease caused by mutations in eukaryotic translation initiation factor 2B (eIF2B). eIF2B mutations predominantly affect the brain white matter, and the characteristic features of VWMD pathology include myelin loss and foamy oligodendrocytes. Activation of pancreatic endoplasmic reticulum kinase (PERK) has been observed in oligodendrocytes in VWMD. PERK activation in response to endoplasmic reticulum stress attenuates eIF2B activity by phosphorylating eIF2␣, suggesting that impaired eIF2B activity in oligodendrocytes induced by VWMD mutations or PERK activation exploit similar mechanisms to promote selective white matter pathology in VWMD. Using transgenic mice that allow for temporally controlled activation of PERK specifically in oligodendrocytes, we discovered that strong PERK activation in oligodendrocytes during development suppressed eIF2B activity and reproduced the characteristic features of VWMD in mice, including hypomyelinating phenotype, foamy oligodendrocytes, and myelin loss. Notably, impaired eIF2B activity induced by PERK activation in oligodendrocytes of fully myelinated adult mice had minimal effects on morphology or function. Our observations point to a cell-autonomous role of impaired eIF2B activity in myelinating oligodendrocytes in the pathogenesis of VWMD.

Methamphetamine interferes with dopamine reuptake, and the resulting increased dopamine oxidation that creates oxidative stress can lead to degeneration of dopaminergic terminals. Previous studies have shown that the trace element selenium protects against methamphetamine toxicity. However, the specific selenoproteins responsible for protection have not been elucidated. Glutathione peroxidases 1 and 4 (GPx1 and GPx4) incorporate selenium into the amino acid selenocysteine, and their known antioxidant functions make them good candidates for protection from methamphetamine-induced oxidative damage. We differentiated SH-SY5Y neuronal cells in serum-free media with defined supplement containing 0, 10 and 100 nM selenium, and then challenged the cells with a 24-hour exposure to methamphetamine. We found that 100 μM methamphetamine decreased GPx1 and GPx4 protein levels. However, both proteins were upregulated with increasing media selenium concentration. GPx enzymatic activity was also increased by selenium and decreased by methamphetamine and correlated with GPx protein levels. Total glutathione levels were reduced by methamphetamine at lower selenium conditions, while the oxidized fraction of GSH was increased at higher selenium levels. Additionally, we observed an increased generation of reactive oxygen species with methamphetamine exposure in media with 0 nM selenium, which was ameliorated by selenium supplementation. These results show that methamphetamine increases oxidative stress by reducing GPx levels, and this can be reversed with addition of selenium. These findings have important implications for treating patients with acute methamphetamine toxicity.

HIV infection and methamphetamine (Meth) abuse both may lead to oxidative stress. This study used HIV-1 transgenic (HIV-1Tg) rats to investigate the independent and combined effects of HIV viral protein expression and low dose repeated Meth exposure on the glutathione (GSH)-centered antioxidant system and oxidative stress in the brain. Total GSH content, gene expression and/or enzymatic activities of glutamylcysteine synthetase (GCS), gamma-glutamyltransferase (GGT), glutathione reductase (GR), glutathione peroxidase (GPx), glutaredoxin (Glrx), and glutathione-s-transferase (GST) were measured. The protein expression of cystine transporter (xCT) and oxidative stress marker 4-hydroxynonenal (HNE) were also analyzed. Brain regions studied include thalamus, frontal and remainder cortex, striatum, cerebellum and hippocampus. HIV-1Tg rats and Meth exposure showed highly regional specific responses. In the F344 rats, the thalamus had the highest baseline GSH concentration and potentially higher GSH recycle rate. HIV-1Tg rats showed high transcriptional responses to GSH depletion in the thalamus. Both HIV-1Tg and Meth resulted in decreased GR activity in thalamus, and decreased Glrx activity in frontal cortex. However, the increased GR and Glrx activities synergized with increased GSH concentration, which might have partially prevented Meth-induced oxidative stress in striatum. Interactive effects between Meth and HIV-1Tg were observed in thalamus on the activities of GCS and GGT, and in thalamus and frontal cortex on Glrx activity and xCT protein expression. Findings suggest that HIV viral protein and low dose repeated Meth exposure have separate and combined effects on the brain’s antioxidant capacity and the oxidative stress response that are regional specific.