A worldwide group of scientists has created an infectious prion disease in a mouse model, in a step that may help unravel the mystery of this progressive disease that affects the nervous system in humans and animals. The research team, including Christina J. Sigurdson, DVM, PhD, assistant professor of pathology at the
The study, led by Dr. Adriano Aguzzi of the
By altering two nucleic acids in the prion gene, the researchers developed a transgenic mouse model that expressed the mutant prion protein. These changes resulted in a "loop" in the protein structure of the mice that was rigid – similar to the structure of the elk prion protein, and unlike the flexible "loop" found in normal mouse or human prion proteins. Aging mice with the "rigid loop" prion protein accumulated plaques in the brain and developed symptoms of neurological disease that are features of prion-related disorders.
"It could be that this 'loop' region of the protein can promote the formation of amyloid plaques in the brain," said Sigurdson. "We also found that by transferring brain tissue from mice with the mutant protein into mice expressing the normal mouse prion protein, we could transmit the neurologic disease between the two groups of animals."
According to Sigurdson, the discovery that an infectious disease can be generated through just two mutations in the prion gene is of particular interest. "Some forms of prion disease in humans caused by genetic mutations have also been shown to be infectious," she said. "This new mouse model of the disease may be useful in our understanding of how the misfolded protein leads to neurodegeneration and for testing new therapies against prion disease."
Additional contributors to the study include K. Peter R. Nilsson, Mathias Heikenwälder, Giuseppe Manco, Petra Schwarz, David Ott, Christian Julius and Jeppe Falsig of the University of Zurich; Simone Hornemann, ETH Zürich; Thomas Rülicke, Austria University of Veterinary Medicine, Vienna; Pawel Liberski, Medical University Lodz, Poland; Lothar Stitz, Friedrich-Loeffler-Institute, Tübingen, Germany; and Kurt Wüthrich, The Scripps Research Institute, La Jolla, CA.
This study was supported by the European Union, the Swiss National Science Foundation, the National Competence Centers for Research on Neural Plasticity and Repair, and on Structural Biology, the National Institutes of Health, the Foundation for Research at the University of Zürich, the US National Prion Research Program, the Knut and Alice Wallenberg Foundation the Bonizzi-Theler Foundation, and by the ETH Zürich.