Inducible overexpression of wild-type prion protein in the muscles leads to a primary myopathy in transgenic mice
- Shenghai Huang†,
- Jingjing Liang†,
- Mengjie Zheng†,
- Xinyi Li†,
- Meiling Wang†,
- Ping Wang†,
- Difernando Vanegas‡,
- Di Wu†,
- Bikram Chakraborty†,
- Arthur P. Hays§,
- Ken Chen¶,
- Shu G. Chen†,
- Stephanie Booth‖,
- Mark Cohen**,
- Pierluigi Gambetti†, and
- Qingzhong Kong†,††
- †Department of Pathology, Case Western Reserve University, Cleveland, OH 44106;
- ‡Department of Cell Biology, Cleveland Clinic Foundation, Cleveland, OH 44195;
- §Department of Pathology, Columbia University Medical Center, New York, NY 10032;
- ¶Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461;
- ‖Division of Host Genetics and Prion Diseases National Microbiology Laboratory, Winnipeg, MB, Canada R3E 3R2; and
- **Institute of Pathology, Case Medical Center, Cleveland, OH 44106
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Edited by Stanley B. Prusiner, University of California, San Francisco, CA, and approved March 6, 2007 (received for review October 6, 2006)
Abstract
The prion protein (PrP) level in muscle has been reported to be elevated in patients with inclusion-body myositis, polymyositis, dermatomyositis, and neurogenic muscle atrophy, but it is not clear whether the elevated PrP accumulation in the muscles is sufficient to cause muscle diseases. We have generated transgenic mice with muscle-specific expression of PrP under extremely tight regulation by doxycycline, and we have demonstrated that doxycycline-induced overexpression of PrP strictly limited to muscles leads to a myopathy characterized by increased variation of myofiber size, centrally located nuclei, and endomysial fibrosis, in the absence of intracytoplasmic inclusions, rimmed vacuoles, or any evidence of a neurogenic disorder. The PrP-induced myopathy correlates with accumulation of an N-terminal truncated PrP fragment in the muscle, and the muscular PrP displayed consistent mild resistance to protease digestion. Our findings indicate that overexpression of wild-type PrP in skeletal muscles is sufficient to cause a primary myopathy with no signs of peripheral neuropathy, possibly due to accumulation of a cytotoxic truncated form of PrP and/or PrP aggregation.
Footnotes
- ††To whom correspondence should be addressed. Email: qxk2{at}case.edu
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Author contributions: Q.K. designed research; S.H., J.L., M.Z., X.L., M.W., P.W., D.V., D.W., B.C., A.P.H., S.G.C., P.G., and Q.K. performed research; K.C. and M.C. contributed new reagents/analytic tools; S.H., A.P.H., S.B., M.C., P.G., and Q.K. analyzed data; and P.G. and Q.K. wrote the paper.
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The authors declare no conflict of interest.
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This article is a PNAS Direct Submission.
- Abbreviations:
- Dox,
- doxycycline;
- PrP,
- prion protein;
- rtTA,
- reverse tetracycline responsive transcription activator;
- Tg,
- transgenic.
- © 2007 by The National Academy of Sciences of the USA
