Oligodendrocytes Are a Major Target of the Toxicity of Spongiogenic Murine Retroviruses

Clase, Amanda C.; Dimcheff, Derek E.; Favara, Cynthia; Dorward, David W.; McAtee, Frank J.; Parrie, Lindsay E.; Ron, David; Portis, John L.

doi:10.2353/ajpath.2006.051357

Cited by 19 publications

(30 citation statements)

References 53 publications

(68 reference statements)

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“…9Axiii). Expression of the ER stress protein, GADD153/CHOP, in oligodendrocytes corroborates recent observations in murine retrovirus-induced oligodendropathy (26). Complementing these findings, Syncytin-1-Tg mice implanted with TNF-␣ displayed significantly lower ASCT1 transcript levels but ASCT2 did not differ between groups.…”

Section: Syncytin-1-tg Animals Show Diminished Myelin Proteins and Nesupporting

confidence: 78%

“…However, Syncytin-1 expression in astrocytes is also induced by an inflammatory milieu, highlighting a vicious cycle with deleterious implications for oligodendrocytes. Moreover, excessive or chronic ER stresses result in apoptotic cell death (31), which is a feature of MS, including mounting evidence for the role of ER stress in affecting oligodendrocyte viability (26). The current studies implicate astrocytes in the pathogenesis of MS, which is plausible assuming the pivotal role of astrocytes in maintaining homeostasis in the CNS through regulation of neuroinflammatory, neurotrophic, and neurotoxic factors (68).…”

Section: Discussionmentioning

confidence: 88%

“…Infection of astrocytes with Moloney MuLV (MoMuLV)-ts1, leads to an ER stress response defined by neuroinflammation and neurodegeneration. In fact, envelope proteins from both the retroviruses, MoMuLV-ts1 and FrCas E , mediate ER stress in the brain (22)(23)(24)(25) and directly affect oligodendrocyte viability by inducing the proapoptotic ER stress gene, GADD153/CHOP (26).…”

Section: Ultiple Sclerosis (Ms)mentioning

confidence: 99%

“…As several retroviral proteins cause neuropathogenic effects through aberrant protein expression (24,26,49), we investigated whether the increased levels of Syncytin-1 in the brains of MS patients (12) contributed to an integrated response leading to cellular pathology. Human fetal astrocytes, which overexpressed Syncytin-1, demonstrated significantly increased transcript levels of GADD153/CHOP, BiP, PERK, ERp57, and OASIS (Fig.…”

Section: Er Chaperones Are Up-regulated In Astrocytes Overexpressing mentioning

confidence: 99%

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The Human Endogenous Retrovirus Envelope Glycoprotein, Syncytin-1, Regulates Neuroinflammation and Its Receptor Expression in Multiple Sclerosis: A Role for Endoplasmic Reticulum Chaperones in Astrocytes

Antony

Ellestad

Hammond

et al. 2007

The Journal of Immunology

126

125

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Retroviral envelopes are pathogenic glycoproteins which cause neuroinflammation, neurodegeneration, and endoplasmic reticulum stress responses. The human endogenous retrovirus (HERV-W) envelope protein, Syncytin-1, is highly expressed in CNS glia of individuals with multiple sclerosis (MS). In this study, we investigated the mechanisms by which Syncytin-1 mediated neuroimmune activation and oligodendrocytes damage. In brain tissue from individuals with MS, ASCT1, a receptor for Syncytin-1 and a neutral amino acid transporter, was selectively suppressed in astrocytes (p < 0.05). Syncytin-1 induced the expression of the endoplasmic reticulum stress sensor, old astrocyte specifically induced substance (OASIS), in cultured astrocytes, similar to findings in MS brains. Overexpression of OASIS in astrocytes increased inducible NO synthase expression but concurrently down-regulated ASCT1 (p < 0.01). Treatment of astrocytes with a NO donor enhanced expression of early growth response 1, with an ensuing reduction in ASCT1 expression (p < 0.05). Small-interfering RNA molecules targeting Syncytin-1 selectively down-regulated its expression, preventing the suppression of ASCT1 and the release of oligodendrocyte cytotoxins by astrocytes. A Syncytin-1-transgenic mouse expressing Syncytin-1 under the glial fibrillary acidic protein promoter demonstrated neuroinflammation, ASCT1 suppression, and diminished levels of myelin proteins in the corpus callosum, consistent with observations in CNS tissues from MS patients together with neurobehavioral abnormalities compared with wild-type littermates (p < 0.05). Thus, Syncytin-1 initiated an OASIS-mediated suppression of ASCT1 in astrocytes through the induction of inducible NO synthase with ensuing oligodendrocyte injury. These studies provide new insights into the role of HERV-mediated neuroinflammation and its contribution to an autoimmune disease.

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Section: Syncytin-1-tg Animals Show Diminished Myelin Proteins and Nesupporting

confidence: 78%

Section: Discussionmentioning

confidence: 88%

Section: Ultiple Sclerosis (Ms)mentioning

confidence: 99%

Section: Er Chaperones Are Up-regulated In Astrocytes Overexpressing mentioning

confidence: 99%

See 2 more Smart Citations

The Human Endogenous Retrovirus Envelope Glycoprotein, Syncytin-1, Regulates Neuroinflammation and Its Receptor Expression in Multiple Sclerosis: A Role for Endoplasmic Reticulum Chaperones in Astrocytes

Antony

Ellestad

Hammond

et al. 2007

The Journal of Immunology

126

125

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“…MLVinduced vacuolar changes are primarily observed in motor system neurons (14)(15)(16), with lesions predominantly involving swollen postsynaptic terminals (14,17). As pathology progresses, glial vacuolation and degeneration are also observed (15,16,18,19).…”

mentioning

confidence: 96%

Ecotropic Murine Leukemia Virus Infection of Glial Progenitors Interferes with Oligodendrocyte Differentiation: Implications for Neurovirulence

Liu

Dunphy

Pedraza

et al. 2016

J Virol

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Certain murine leukemia viruses (MLVs) are capable of inducing fatal progressive spongiform motor neuron disease in mice that is largely mediated by viral Env glycoprotein expression within central nervous system (CNS) glia. While the etiologic mechanisms and the glial subtypes involved remain unresolved, infection of NG2 glia was recently observed to correlate spatially and temporally with altered neuronal physiology and spongiogenesis. Since one role of NG2 cells is to serve as oligodendrocyte (OL) progenitor cells (OPCs), we examined here whether their infection by neurovirulent (FrCasE) or nonneurovirulent (Fr57E) ecotropic MLVs influenced their viability and/or differentiation. Here, we demonstrate that OPCs, but not OLs, are major CNS targets of both FrCasE and Fr57E. We also show that MLV infection of neural progenitor cells (NPCs) in culture did not affect survival, proliferation, or OPC progenitor marker expression but suppressed certain glial differentiation markers. Assessment of glial differentiation in vivo using transplanted transgenic NPCs showed that, while MLVs did not affect cellular engraftment or survival, they did inhibit OL differentiation, irrespective of MLV neurovirulence. In addition, in chimeric brains, where FrCasEinfected NPC transplants caused neurodegeneration, the transplanted NPCs proliferated. These results suggest that MLV infection is not directly cytotoxic to OPCs but rather acts to interfere with OL differentiation. Since both FrCasE and Fr57E viruses restrict OL differentiation but only FrCasE induces overt neurodegeneration, restriction of OL maturation alone cannot account for neuropathogenesis. Instead neurodegeneration may involve a two-hit scenario where interference with OPC differentiation combined with glial Env-induced neuronal hyperexcitability precipitates disease. IMPORTANCEA variety of human and animal retroviruses are capable of causing central nervous system (CNS) neurodegeneration manifested as motor and cognitive deficits. These retroviruses infect a variety of CNS cell types; however, the specific role each cell type plays in neuropathogenesis remains to be established. The NG2 glia, whose CNS functions are only now emerging, are a newly appreciated viral target in murine leukemia virus (MLV)-induced neurodegeneration. Since one role of NG2 glia is that of oligodendrocyte progenitor cells (OPCs), we investigated here whether their infection by the neurovirulent MLV FrCasE contributed to neurodegeneration by affecting OPC viability and/or development. Our results show that both neurovirulent and nonneurovirulent MLVs interfere with oligodendrocyte differentiation. Thus, NG2 glial infection could contribute to neurodegeneration by preventing myelin formation and/or repair and by suspending OPCs in a state of persistent susceptibility to excitotoxic insult mediated by neurovirulent virus effects on other glial subtypes.A variety of murine leukemia viruses (MLVs) are capable of inducing noninflammatory neurodegeneration upon infection of the central ne...

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Cytopathology of Viral Diseases

Cheville¹,

Lehmkuhl

2009

Ultrastructural Pathology the Comparative Cellular Basis of Disease

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Oligodendrocytes Are a Major Target of the Toxicity of Spongiogenic Murine Retroviruses

Cited by 19 publications

References 53 publications

The Human Endogenous Retrovirus Envelope Glycoprotein, Syncytin-1, Regulates Neuroinflammation and Its Receptor Expression in Multiple Sclerosis: A Role for Endoplasmic Reticulum Chaperones in Astrocytes

The Human Endogenous Retrovirus Envelope Glycoprotein, Syncytin-1, Regulates Neuroinflammation and Its Receptor Expression in Multiple Sclerosis: A Role for Endoplasmic Reticulum Chaperones in Astrocytes

Ecotropic Murine Leukemia Virus Infection of Glial Progenitors Interferes with Oligodendrocyte Differentiation: Implications for Neurovirulence

Cytopathology of Viral Diseases

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