Disparate Regions of Envelope Protein Regulate Syncytium Formation versus Spongiform Encephalopathy in Neurological Disease Induced by Murine Leukemia Virus TR

Murphy, Samuel L.; Honczarenko, Marek; Dugger, Natalie V.; Hoffman, Paul M.; Gaulton, Glen N.

doi:10.1128/jvi.78.15.8392-8399.2004

Cited by 11 publications

(7 citation statements)

References 51 publications

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“…3) it was apparent that retroviral neurovirulence was dependent on the presence of RBD sequences from CasBrE. This obser- vation is consistent with mapping studies that have been carried out on other neurovirulent murine retroviruses (35,36,39,48). However, the presence of the RBD from CasBrE was not sufficient to generate a virus with neurovirulence comparable to that of FrCas NC .…”

Section: Discussionsupporting

confidence: 77%

The Degree of Folding Instability of the Envelope Protein of a Neurovirulent Murine Retrovirus Correlates with the Severity of the Neurological Disease

Portis

Askovich

Austin

et al. 2009

J Virol

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A small group of ecotropic murine retroviruses cause a spongiform neurodegenerative disease manifested by tremor, paralysis, and wasting. The neurovirulence of these viruses has long been known to be determined by the sequence of the viral envelope protein, although the nature of the neurotoxicity remains to be clarified. Studies on the neurovirulent viruses FrCas NC and Moloney murine leukemia virus ts1 indicate that the nascent envelope protein misfolds, is retained in the endoplasmic reticulum (ER), and induces an unfolded protein response. In the present study we constructed a series of viruses with chimeric envelope genes containing segments from virulent and avirulent retroviruses. Each of the viruses studied was highly neuroinvasive but differed in the severity of the neurological disease they induced. Only viruses that contained the receptorbinding domain (RBD) of the neurovirulent virus induced neurological disease. Likewise, only viruses containing the RBD of the neurovirulent virus exhibited increased binding of the ER chaperone BiP to the envelope precursor protein and induced the unfolded protein response. Thus, the RBD determined both neurovirulence and folding instability. Among viruses carrying the neurovirulent RBD, the severity of the disease was increased when envelope sequences from the neurovirulent virus outside the RBD were also present. Interestingly, these sequences appeared to further increase the degree of folding instability (BiP binding) of the viral envelope protein. These results provide strong support for the hypothesis that this spongiform neurodegenerative disease represents a virus-induced protein folding disorder.

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Section: Discussionsupporting

confidence: 77%

The Degree of Folding Instability of the Envelope Protein of a Neurovirulent Murine Retrovirus Correlates with the Severity of the Neurological Disease

Portis

Askovich

Austin

et al. 2009

J Virol

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“…TR1.3 MuLV infection produced multiple small brain lesions in immature mice, because of viral damage within small arteries (Park et al, 1993(Park et al, , 1994Murphy et al, 2004). Neonatal pups were injected intraperitoneally or intracerebrally with virus suspension on postnatal day 1 to 3 (animals become resistant after day 4).…”

Section: Models Based On Damage To Blood Vesselsmentioning

confidence: 99%

Doin vivoExperimental Models Reflect Human Cerebral Small Vessel Disease? a Systematic Review

Hainsworth

Markus

2008

J Cereb Blood Flow Metab

228

204

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Cerebral small vessel disease (SVD) is a major cause of stroke and dementia. Pathologically, three lesions are seen: small vessel arteriopathy, lacunar infarction, and diffuse white matter injury (leukoaraiosis). Appropriate experimental models would aid in understanding these pathologic states and also in preclinical testing of therapies. The objective was to perform a systematic review of animal models of SVD and determine whether these resemble four key clinicopathologic features: (1) small, discrete infarcts; (2) small vessel arteriopathy; (3) diffuse white matter damage; (4) cognitive impairment. Fifteen different models were included, under four categories: (1) embolic injuries (injected blood clot, photochemical, detergent-evoked); (2) hypoperfusion/ischaemic injury (bilateral common carotid occlusion/stenosis, striatal endothelin-1 injection, striatal mitotoxin 3-NPA); (3) hypertension-based injuries (surgical narrowing of the aorta, or genetic mutations, usually in the renin-angiotensin system); (4) blood vessel damage (injected proteases, endotheliumtargeting viral infection, or genetic mutations affecting vessel walls). Chronic hypertensive models resembled most key features of SVD, and shared the major risk factors of hypertension and age with human SVD. The most-used model was the stroke-prone spontaneously hypertensive rat (SHR-SP). No model described all features of the human disease. The optimal choice of model depends on the aspect of pathophysiology being studied.

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“…Mice inoculated with virus after postnatal day 10 are completely resistant to the disease. Since the original description and cloning of CasBrE, a number of other viral strains have been isolated in the laboratory that cause similar diseases both in mice 3,4 and rats. 5,6 For each of these viruses, neurovirulence is dependent on the sequence of the envelope protein, 7 although the nature of the neurotoxicity is unclear.…”

mentioning

confidence: 99%

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

Clase

Dimcheff

Favara

et al. 2006

The American Journal of Pathology

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The neurovirulent retroviruses FrCasE and Moloney MLV-ts1 cause noninflammatory spongiform neurodegeneration in mice, manifested clinically by progressive spasticity and paralysis. Neurons have been thought to be the primary target of toxicity of these viruses. However the neurons themselves appear not to be infected, and the possible indirect mechanisms driving the neuronal toxicity have remained enigmatic. Here we have re-examined the cells that are damaged by these viruses, using lineage-specific markers. Surprisingly, these cells expressed the basic helix-loop-helix transcription factor Olig2, placing them in the oligodendrocyte lineage.

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Disparate Regions of Envelope Protein Regulate Syncytium Formation versus Spongiform Encephalopathy in Neurological Disease Induced by Murine Leukemia Virus TR

Cited by 11 publications

References 51 publications

The Degree of Folding Instability of the Envelope Protein of a Neurovirulent Murine Retrovirus Correlates with the Severity of the Neurological Disease

The Degree of Folding Instability of the Envelope Protein of a Neurovirulent Murine Retrovirus Correlates with the Severity of the Neurological Disease

Doin vivoExperimental Models Reflect Human Cerebral Small Vessel Disease? a Systematic Review

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

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