Search

Highlights: [•] miRs expression profiling shown 20 miRs deregulated in affected rats. [•] miR-132 level was increased in affected rats. [•] Nurr1 protein level was decreased in mesencephalic neurons of affected rats. [•] BDNF serum and mesencephalic brain tissue levels were decreased in affected rats. [ABSTRACT FROM AUTHOR]

J. Neurochem. (2012) 122, 812-822. Abstract Neuronal protein α-synuclein (α-syn) is an essential player in the development of neurodegenerative diseases called synucleinopathies. A spontaneous autosomal recessive rat model for neurodegeneration was developed in our laboratory. These rats demonstrate progressive increases in α-syn in the brain mesencephalon followed by loss of dopaminergic terminals in the basal ganglia (BG) and motor impairments. The severity of pathology is directly related to the overexpression of α-syn and parallel decrease in dopamine (DA) level in the striatum (ST) of affected rats. The neurodegeneration in this model is characterized by the presence of perikarya and neurites Lewis bodies (LB) and diffuse marked accumulation of perikaryal α-syn in the substantia nigra (SN), brain stem (BS), and striatum (ST) along with neuronal loss. Light and ultrastructural analyses revealed that the process of neuronal degeneration is a 'dying back' type. The disease process is accompanied by gliosis and release of inflammatory cytokines. This neurodegeneration is a multisystemic disease and implicate α-syn as a major factor in the pathogenesis of this inherited autosomal recessive animal model. Decrease dopamine (DA) and overexpression of α-syn in the brain mesencephalon may provide a naturally occurring animal model for Parkinson's disease (PD) and other synucleinopathies that reproduces significant pathological, neurochemical, and behavioral features of the human disease. [ABSTRACT FROM AUTHOR]

Moloney murine leukemia virus-temperature sensitive (MoMuLV-ts1)-mediated neuronal death is a result of both loss of glial support and release of cytokines and neurotoxins from ts1-infected glial cells. Here the authors propose vascular endothelial growth factor (VEGF) down-regulation as another contributory factor in neuronal degeneration induced by ts1 infection. To determine how ts1 affects VEGF expression in ts1-infected brain, the authors examined the expression of several proteins that are important in regulating the expression of VEGF. The authors found significant decreases in Jun-activating domain-binding protein 1 (Jab1), hypoxia-inducible factor (HIF)-1α, and VEGF levels and increases in p53 protein levels in ts1-infected brains compared to noninfected control brains. The authors suggest that a decrease Jab1 expression in ts1 infection leads to accumulation of p53, which binds to HIF-1α to accelerate its degradation. A rapid degradation of HIF-1α leads to decreased VEGF production and secretion. Considering that endothelial cells are the most conspicuous in virus replication and production in ts1 infection, but are not killed by the infection, the authors examined the expression of these proteins using infected and noninfected mouse cerebrovascular endothelial (CVE) cells. The ts1- infected CVE cells showed decreased Jab1, HIF-1α, and VEGF mRNA and protein levels and increased p53 protein levels compared with noninfected cells, consistent with the results found in vivo. These results confirm that ts1 infection results in insufficient secretion of VEGF from endothelial cells and may result in decreased neuroprotection. This study suggested that ts1-mediated neuropathology in mice may result from changes in expression and activity of Jab1, p53, and HIF-1α, with a final target on VEGF expression and neuronal degeneration. [ABSTRACT FROM AUTHOR]

Abstract: Ataxia telangiectasia (A-T) is an inherited disease, the most prominent feature of which is ataxia caused by degeneration of cerebellar neurons and synapses. The mechanisms underlying A-T neurodegeneration are still unclear, and many factors are likely to be involved. AMP-activated protein kinase (AMPK) is a sensor of energy balance, and research on its function in neural cells has gained momentum in the last decade. The dual roles of AMPK in neuroprotection and neurodegeneration are complex, and they need to be identified and characterized. Using an Atm (ataxia telangiectasia mutated) gene deficient mouse model, we showed here that: (a) upregulation of AMPK phosphorylation and elevation of reactive oxygen species (ROS) coordinately occur in the cerebella of Atm−/− mice; (b) hydrogen peroxide induces AMPK phosphorylation in primary mouse cerebellar astrocytes in an Atm-independent manner; (c) administration of the novel antioxidant monosodium luminol (MSL) to Atm−/− mice attenuates the upregulation of both phosphorylated-AMPK (p-AMPK) and ROS, and corrects the neuromotor deficits in these animals. Together, our results suggest that oxidative activation of AMPK in the cerebellum may contribute to the neurodegeneration in Atm−/− mice, and that ROS and AMPK signaling pathways are promising therapeutic targets for treatment of A-T and other neurodegenerative diseases. [Copyright &y& Elsevier]

Abstract: Oxidative stress is implicated in various kinds of neurological disorders, including human immunodeficiency virus (HIV) associated dementia (HAD). Our laboratory has been studying the murine retrovirus ts1, a pathogenic mutant of the Moloney murine leukemia virus (MoMuLV), as a model for HAD. Like HIV in humans, ts1 induces oxidative stress and progressive neurodegeneration in mice. We have shown previously that an antioxidant and anti-inflammatory drug GVT or MSL (monosodium luminol) suppresses ts1-induced oxidative stress, attenuates the development of spongiform encephalopathy, and delays hind limb paralysis in infected mice. It is known that upregulation of the nuclear transcription factor NF-E2-related factor 2 (Nrf2) is involved in upregulating cellular antioxidant defenses. Since Nrf2 is associated with elevation of antioxidant defenses in general, and since GVT suppresses ts1-induced neurodegeneration, our aim in this study was to determine whether GVT neuroprotection is linked to Nrf2 upregulation in the brain. We report here that GVT upregulates the levels of Nrf2, both in primary astrocyte cultures and in brainstem of ts1-infected mice. Significant upregulation of Nrf2 expression by GVT occurs in both the cytosolic and nuclear fractions of cultured astrocytes and brainstem cells. Notably, although GVT treatment increases Nrf2 protein levels in cultured astrocytes and brainstem tissues, Nrf2 mRNA levels are not altered. This suggests that the neuroprotective effects of GVT may be mediated by the stabilization of the Nrf2 protein, allowing continuous upregulation of Nrf2 levels in the astrocytes. [Copyright &y& Elsevier]

Abstract: The ts1 mutant of the Moloney murine leukemia virus (MoMuLV) causes neurodegeneration in infected mice that resembles HIV-associated dementia. We have shown previously that ts1 infects glial cells in the brain, but not neurons. The most likely mechanism for ts1-mediated neurodegeneration is loss of glial redox support and glial cell toxicity to neurons. Minocycline has been shown to have neuroprotective effects in various models of neurodegeneration. This study was designed to determine whether and how minocycline prevents paralysis and death in ts1-infected mice. We show here that minocycline delays neurodegeneration in ts1-infected mice, and that it prevents death of cultured astrocytes infected by ts1 through attenuating oxidative stress, inflammation and apoptosis. Although minocycline reduces virus titers in the CNS of infected mice, it does not affect virus titers in infected mice thymi, spleens or infected C1 astrocytes. In addition, minocycline prevents death of primary neurons when they are cocultured with ts1-infected astrocytes, through mechanisms involving both inhibition of oxidative stress and upregulation of the transcription factor NF-E2-related factor 2 (Nrf2), which controls cellular antioxidant defenses. We conclude that minocycline delays retrovirus ts1-induced neurodegeneration involving antioxidant, anti-inflammation and anti-apoptotic mechanisms. [Copyright &y& Elsevier]