The retrovirus tsl, a mutant of Moloney murine leukemia virus, like HIV infection in human, causes a progressive neuroimmunodegenerative (NID) syndrome in mice. Infection in the central nervous system by tsl results in neuronal loss with gliosis and spongiform lesions. Since glial cells but not neurons are infected with the virus, the neuropathogenic mechanism of tsl, like those of HIV, are most likely indirect. We previously demonstrated that accumulation of tsl precursor envelope proteins occurs in the endoplasmic reticulum (ER) of tsl infected astrocytes. This accumulation is accompanied by cell death in tsl-infected astrocytes. We also observed intracellular calcium accumulation and activation of NFkappaB in both astrocytes and neurons m the area of lesions in the CNS of tsl- infected mice. We therefore hypothesize that the excessive accumulation of tsl precursor envelope proteins in the astrocytic ER activates ER overload response resulting in excessive Ca2+ release that uncouples mitochondria causing release of toxic reactive oxygen species (ROS). In the CNS of tsl-infected mice there is a significant reduction of cysteine levels. A consequence of cysteine deficiency is the decrease in intracellular glutathione, which provides the major antioxidant defense in cells. This together with our recent finding that tsl decreases catalase levels in infected astrocytes and CNS suggests that the defense against oxidative stress in astrocytes and in the CNS is deficient. The oxidative damaged astrocytes may fail to support the developing neurons, and the release of ROS from astrocytes may also result in damage to neuronal membrane. Both of these effects could in turn result in neuronal death. Glutathione precursor N-acetyl cysteine, or peroxisome proliferator that activate production of catalase, have been shown to ameliorate both the tsl-induced astrocytic death in vitro and to prolong the latency period of tsl-induced neurodegeneration in vivo. Based on these preliminary observations we therefore propose here to: 1) Determine whether tsl induces thiol deficiency and oxidative damage in astrocytes in culture and in the CNS, 2) Elucidate the mechanisms underlying tsl-mediated thiol deficiency and redox stress in astrocytes and neurons in culture and in the CNS, and 3) Determine whether (a) NAC, (b) alpha-lipoic acid/dihydrolipoic acid, (c) peroxisome proliferators, such as PBA, that generate catalase, and (d) other antioxidants, e.g. Oxothiazolidine-4-carboxylate (OTC), either alone or in combination, can prevent or ameliorate tsl-induced astrocyte damage and neurodegeneration in the CNS. This project is focused on a well-characterized animal model. It addresses questions critical to our understanding of thiol deficiency and oxidative stress in retroviral-induced encephalopathy. It also provides a therapeutic rationale for controlling retroviral- induced neurodegeneration

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS043984-03
Application #
6754502
Study Section
Special Emphasis Panel (ZRG1-AARR-1 (05))
Program Officer
Nunn, Michael
Project Start
2002-06-18
Project End
2006-05-31
Budget Start
2004-06-01
Budget End
2005-05-31
Support Year
3
Fiscal Year
2004
Total Cost
$327,195
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Organized Research Units
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Kim, Soo Jin; Wong, Paul K Y (2015) p53 as a retrovirus-induced oxidative stress modulator. J Gen Virol 96:144-9
Kim, Soo Jin; Wong, Paul K Y (2013) ROS upregulation during the early phase of retroviral infection plays an important role in viral establishment in the host cell. J Gen Virol 94:2309-17
Reddy, Pichili Vijaya Bhaskar; Lungu, Gina; Kuang, Xianghong et al. (2010) Neuroprotective effects of the drug GVT (monosodium luminol) are mediated by the stabilization of Nrf2 in astrocytes. Neurochem Int 56:780-8
Lungu, G; Kuang, X; Stoica, G et al. (2010) Monosodium luminol upregulates the expression of Bcl-2 and VEGF in retrovirus-infected mice through downregulation of corresponding miRNAs. Acta Virol 54:27-32
Kuang, Xianghong; Hu, Wenhui; Yan, Mingshan et al. (2010) Phenylbutyric acid suppresses protein accumulation-mediated ER stress in retrovirus-infected astrocytes and delays onset of paralysis in infected mice. Neurochem Int 57:738-48
Scofield, Virginia L; Yan, Mingshan; Kuang, Xianghong et al. (2009) The drug monosodium luminol (GVT) preserves crypt-villus epithelial organization and allows survival of intestinal T cells in mice infected with the ts1 retrovirus. Immunol Lett 122:150-8
Kuang, Xianghong; Scofield, Virginia L; Yan, Mingshan et al. (2009) Attenuation of oxidative stress, inflammation and apoptosis by minocycline prevents retrovirus-induced neurodegeneration in mice. Brain Res 1286:174-84
Scofield, Virginia L; Yan, Mingshan; Kuang, Xianghong et al. (2009) The drug monosodium luminol (GVT) preserves thymic epithelial cell cytoarchitecture and allows thymocyte survival in mice infected with the T cell-tropic, cytopathic retrovirus ts1. Immunol Lett 122:159-69
Lungu, Gina F; Stoica, George; Wong, Paul K Y (2008) Down-regulation of Jab1, HIF-1alpha, and VEGF by Moloney murine leukemia virus-ts1 infection: a possible cause of neurodegeneration. J Neurovirol 14:239-51
Stoica, George; Lungu, Gina; Kim, Hun-Taek et al. (2008) Up-regulation of pro-nerve growth factor, neurotrophin receptor p75, and sortilin is associated with retrovirus-induced spongiform encephalomyelopathy. Brain Res 1208:204-16

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