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Journal of Virology, July 2003, p. 7193-7201, Vol. 77, No. 13
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.13.7193-7201.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Effects of Mutant Ubiquitin on ts1 Retrovirus-Mediated Neuropathology

Mei Zhang,1 Sherry Thurig,1 Maria Tsirigotis,1,2 Paul K. Y. Wong,3 Kenneth R. Reuhl,4 and Douglas A. Gray1,2*

Centre for Cancer Therapeutics, Ottawa Regional Cancer Centre, Ottawa, Ontario, Canada K1H 1C4,1 Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5,2 Science Park, Research Division, The University of Texas M.D. Anderson Cancer Centre, Smithville, Texas,3 Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey4

Received 5 November 2002/ Accepted 2 April 2003

ts1 is a temperature-sensitive mutant of Moloney murine leukemia virus that induces a rapid spongiform encephalopathy in mice infected as newborns. The pathological features include the formation of ubiquitinated inclusions resembling Lewy bodies. To determine how perturbation of the ubiquitin-proteasome pathway might affect ts1-mediated neurodegeneration, the virus was introduced into transgenic mice in which the assembly of ubiquitin chains was compromised by the expression of dominant-negative mutant ubiquitin. The onset of symptoms was greatly delayed in a transgenic mouse line expressing K48R mutant ubiquitin; no such delay was observed in mice expressing a wild-type ubiquitin transgene or K63R mutant ubiquitin. The extended latency was found to correlate with a delayed increase in viral titers. Pathological findings in K48R transgenic mice at 60 days were found to be similar to those in the other strains at 30 days, suggesting that while delayed, the neurodegenerative process in K48R mice was otherwise similar. These data demonstrate the sensitivity of retroviral replication to the partial disruption of ubiquitin-mediated proteolysis in vivo, a finding that may have therapeutic potential.

* Corresponding author. Mailing address: Centre for Cancer Therapeutics, Ottawa Regional Cancer Centre, 503 Smyth Rd., Ottawa, Ontario, Canada K1H 1C4. Phone: (613) 737-7700, ext. 6896. Fax: (613) 247-3524. E-mail: Doug.Gray{at}orcc.on.ca.

Journal of Virology, July 2003, p. 7193-7201, Vol. 77, No. 13
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.13.7193-7201.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Rasoulpour, R. J., Schoenfeld, H. A., Gray, D. A., Boekelheide, K. (2003). Expression of a K48R Mutant Ubiquitin Protects Mouse Testis from Cryptorchid Injury and Aging. Am. J. Pathol. 163: 2595-2603 [Abstract] [Full Text]  


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