Hippocampal Poly(ADP-Ribose) Polymerase 1 and Caspase 3 Activation in Neonatal Bornavirus Infection

Abstract

Infection of neonatal rats with Borna disease virus results in a characteristic behavioral syndrome and apoptosis of subsets of neurons in the hippocampus, cerebellum, and cortex (neonatal Borna disease [NBD]).In the NBD rat hippocampus, dentate gyrus granule cells progressively degenerate. Apoptotic loss of granule cells in NBD is associated with accumulation of zinc in degenerating neurons and reduced zinc in granule cell mossy fibers. Excess zinc can trigger poly(ADP-ribose) polymerase 1 (PARP-1) activation, and PARP-1 activation can mediate neuronal death. Here, we evaluate hippocampal PARP-1 mRNA and protein expression levels, activation, and cleavage, as well as apoptosis-inducing factor (AIF) nuclear translocation and executioner caspase 3 activation, in NBD rats. PARP-1 mRNA and protein levels were increased in NBD hippocampi. PARP-1 expression and activity were increased in granule cell neurons and glia with enhanced ribosylation of proteins, including PARP-1 itself. In contrast, levels of poly(ADP-ribose) glycohydrolase mRNA were decreased in NBD hippocampi. PARP-1 cleavage and AIF expression were also increased in astrocytes in NBD hippocampi. Levels of activated caspase 3 protein were increased in NBD hippocampi and localized to nuclei, mossy fibers, and dendrites of granule cell neurons. These results implicate aberrant zinc homeostasis, PARP-1, and caspase 3 activation as contributing factors in hippocampal neurodegeneration in NBD.Borna disease virus (BDV) is a nonsegmented, negativesense, single-stranded RNA virus that persistently infects the central nervous systems (CNS) of and causes behavioral disturbances in a wide range of mammalian and avian species (18,25). Experimental infection of adult immunocompetent Lewis rats causes a severe meningoencephalitis and a progressive movement disorder that may be associated with detected alterations of the dopamine system and immune-mediated damage (29, 52). In contrast, newborn rats infected with BDV (neonatal borna disease [NBD]) do not mount an overt cellular immune response yet have prominent neuronal loss; pronounced astrogliosis and microgliosis; altered cytokine, neurotrophic factor, and neurotrophic factor receptor gene expression; abnormal development of brain monoaminergic systems; neuronal and astrocytic endoplasmic reticulum (ER) stress; and disturbances of learning, mood, and behavior (11,31,38,45,62,67). Although BDV is noncytolytic, NBD is attended by apoptotic degeneration of neurons that undergo substantial postnatal maturation, especially in the hippocampus (HC), cerebellum (CBLM), and cortex (31, 60). Neuronal loss in the CBLM is associated with the induction of ER stress in Purkinje cells, expression of the proapototic molecule C/EBP homologous protein (CHOP), and deficient expression of ER quality control molecules. However, apoptosis of HC dentate gyrus granule cell neurons (DGNs) is not associated with the clear signs of ER disturbances found in other brain regions (62). Thus, the molecular mechanisms contributing to HC neurodegene...

Borna Disease Virus Infects Human Neural Progenitor Cells and Impairs Neurogenesis

“…Our findings support the hypothesis that BDV-induced neurodegeneration is due to BDV interference with neurogenesis. In support of this theory, similar caspase 3-dependent apoptotic mechanisms have been demonstrated in vitro and in vivo (43). We cannot, however, exclude that other mechanisms also contribute to BDV-induced neuropathogenesis in vivo.…”

Persistent human Borna disease virus infection modifies the acetylome of human oligodendroglia cells towards higher energy and transporter levels

“…Although neurons are the primary targets of BDV, astroglia and oligodendroglia can be infected by BDV as well (Carbone et al, 1993). As our previous study and others have shown, various cell types react differently to different BDV viral strains Poenisch et al, 2009;Williams et al, 2008;Wu et al, 2013). Moreover, in virus-host interactions, several specific acetylation sites have been demonstrated to play pivotal roles (Huo et al, 2011;Lammers et al, 2010;Oussaief et al, 2009).…”

Notch/HES1-mediated PARP1 activation: a cell type–specific mechanism for tumor suppression

“…25 PARP1 activation can also mediate neuronal death through enhanced self-ribosylation and cleavage of PARP1 and subsequent nuclear translocation of apoptosis-inducing factor (AIF), 28 resulting in activation of the caspase cascade. 29 Finally, PARP1 binds to and modulates the activity of various transcription factors. 24,30,31 Most relevant to this study, interaction of PARP1 with HES1 promotes phosphorylation of HES1 by Ca ϩ /calmodulin-dependent protein kinase II with subsequent displacement of TLE co-repressors and recruitment of coactivators, resulting in formation of new transcriptional complex and result in HES1-mediated transactivation rather than repression of its target genes in rat neural stem cells.…”