Role for glutathione peroxidase-4 in brain development and neuronal apoptosis: specific induction of enzyme expression in reactive astrocytes following brain injury

Abstract

Glutathione peroxidase-4 (GPx4) is a multifunctional selenoprotein expressed as mitochondrial, cytosolic, or nuclear isoforms. As a catalytically active enzyme it has been implicated in antioxidative defense, but during sperm development it functions as a structural protein. GPx4 null mice die in utero at midgestation and knockdown of GPx4 during embryogenesis disturbs brain development. To explore the cerebral function of GPx4 we profiled cell-specific enzyme expression at various stages of perinatal brain maturation and investigated its regulation following brain injury by immunohistochemistry, in situ hybridization, and quantitative RT-PCR. Large amounts of GPx4 mRNA were detected in all neuronal layers during perinatal brain development but expression became restricted during postnatal maturation. In adult brain mitochondrial and cytosolic GPx4 isoforms were detected in neurons of cerebral cortex, hippocampus, and cerebellum whereas glial cells were devoid of GPx4. Following selective brain injury expression of the enzyme was upregulated in reactive astrocytes of lesioned areas and deafferented regions but not in neurons. Selective knockdown of GPx4 by small interfering RNA induced depletion of phosphatidylinositol-(4,5)-bisphosphate in the neuronal plasma membrane and subsequently apoptosis as indicated by caspase-3 activation. We hypothesize that astrocytic upregulation of GPx4 in response to injury is part of a protective cascade counteracting further cell damage.