Endoplasmic Reticulum Stress and Neurodegeneration in Rats Neonatally Infected with Borna Disease Virus

Abstract

Borna disease virus infection of neonatal rats results in a characteristicBorna disease virus (BDV) is a nonsegmented, negativesense, single-stranded RNA virus belonging to the virus family Bornaviridae within the order Mononegavirales (5, 11). Experimental infection of adult immunocompetent Lewis rats results in a marked CD8 ϩ immune response (meningoencephalitis) and a progressive movement disorder (20). In contrast, newborn rats infected with BDV (neonatal Borna disease [NBD]) do not mount an overt cellular immune response yet have prominent astrogliosis and microgliosis, altered cytokine, neurotrophic factor, and neurotrophic factor receptor gene expression, abnormal development of brain monoaminergic systems, cerebellar and hippocampal dysgenesis, and disturbances of learning, mood, and behavior (8,25,47,54). Although BDV is noncytolytic, NBD is attended by apoptotic degeneration of neurons in the cerebellum (CBLM) and hippocampus (HC) that undergo substantial postnatal maturation (25,72). However, the cellular and molecular mechanisms leading to neurodegeneration in NBD remain unclear.The endoplasmic reticulum (ER) plays a vital role in a variety of cellular functions, including synthesis, folding, and posttranslational modification of secretory and membrane proteins, cytoplasmic and mitochondrial metabolism, homeostasis of intracellular calcium, and apoptosis. The ER is sensitive to nutrient or energy deprivation, disruption of calcium homeostasis, inhibition of N-linked glycosylation, oxidative stress, and accumulation of unfolded, misfolded, or excessive protein (61, 69). Perturbations causing ER stress result in accumulation of unfolded proteins in the ER lumen and initiation of a complex signal transduction cascade, known as the unfolded protein response (UPR) (Fig.

Both endoplasmic reticulum and mitochondria are involved in disc cell apoptosis and intervertebral disc degeneration in rats

“…Because ER stress is so crucial to cell survival or death, it has become an attractive research focus in recent years. In fact, there is a great body of evidence indicating that apoptosis mediated by ER plays an important role in degenerative diseases such as Alzheimer's disease (Unterberger et al 2006;Williams and Lipkin 2006), amyotrophic lateral sclerosis (Nagata et al 2007), senile cataract (Mulhern et al 2006), and osteoarthritis (Oliver et al 2005;Yang et al 2005).…”

Initiation and execution of lipotoxic ER stress in pancreatic β-cells

“…CHOP, by contrast, contributes to the initiation of palmitate-induced β-cell apoptosis. Several studies point to a pro-apoptotic effect of CHOP downstream of irremediable ER stress (Benavides et al, 2005;Oyadomari and Mori, 2004;Tajiri et al, 2006), but this effect might depend on the parallel expression of other components of the ER stress response (Williams and Lipkin, 2006). Most ER-stress-related pro-apoptotic signals ultimately lead to caspase activation (Rao et al, 2004).…”

Mutations in Cx30 that are linked to skin disease and non-syndromic hearing loss exhibit several distinct cellular pathologies

“…To determine whether expression of the Cx30 V37E mutant activates the IRE1 arm of the UPR, we performed an X-box binding protein 1 (XBP1) splicing assay (Calfon et al, 2002;Williams and Lipkin, 2006). In response to unfolded proteins, IRE1 directly splices a small intron from XBP1 mRNA (Ron and Walter, 2007), which contains a single PstI restriction site (supplementary material Fig.…”

“…Processing of XBP1 mRNA, a marker of ER stress, was detected by PCR and restriction site analysis, as described elsewhere (Williams and Lipkin, 2006). Briefly, REKs were transfected with cDNA encoding wild-type Cx30 or the mutant proteins 12-24 hours before RNA extraction.…”