The discovery is reported in the August 27 edition of the journal Neuron.
Until now, two theories about the role mutations play in prion diseases have been at odds. According to one theory, mutations make carriers more susceptible to prions in the environment. Alternatively, mutations themselves might cause the disease and the spontaneous generation of transmissible prions.
Prions cause several diseases, including Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalitis (BSE, or "mad cow disease") in cows, and scrapie in sheep. Some prion diseases, like BSE, can be transmitted from feed animals to humans. Deciphering the origins of prion diseases could help farmers and policy-makers determine how best to control a prion disease outbreak in livestock and to prevent prion transmission to humans.
Prions are misfolded versions of a protein called PrP. In its normal form, PrP is expressed in the brain and other neural tissues. But specific events, such as exposure to prions from the environment, can cause PrP to change from its normal shape to that of a prion. Once in the prion shape, the protein can convert other normal PrP proteins to the abnormal shape. As PrP proteins convert to prions, they form long chains that damage brain and nerve cells, causing the neurodegenerative and behavioral symptoms characteristic of prion diseases.
To determine if a mutation in the PrP gene can cause a transmissible prion disease, Walker Jackson, first author of the Neuron article and a postdoctoral researcher in the lab of Whitehead Member Susan Lindquist, engineered a knock-in mouse expressing a PrP gene carrying the mutation associated with the human prion disease fatal familial insomnia (FFI).
In knock-in experiments, the researcher removes a gene of interest, makes specific changes to it in a test tube, and then places it back in its original place in the genome. In this case, Jackson replaced the mouse PrP gene with an altered version carrying the FFI mutation. This version also carried a sequence from human PrP that prevented the mice from acquiring normal mouse prions that could potentially be in the environment.
"It's more difficult to create a knock-in mouse, instead of randomly integrating the mutated gene into the mouse's genome," says Jackson. "But creating a knock-in like this makes sure the gene is expressed when and where it normally would be. That's the number one reason we think this disease model worked so well, compared to others' experiments."
As adults, the mice exhibited many of the same traits as human FFI patients: reduced activity levels and sleep abnormalities. When Jackson examined the mice's brains, they resembled those of human FFI patients, with prominent damage to the thalamic region of the brain.
After establishing that the mice have the behavioral and pathological characteristics of FFI, Jackson injected diseased brain tissue from the FFI mice into healthy mice. The healthy mice also carried the same human derived barrier as the FFI mice, preventing their infection by normal mouse prions and ensuring that the only prion they could acquire was the one engineered by Jackson. After injection with the affected tissue, the healthy mice exhibited similar symptoms and neuropathology as the mice with the FFI mutation.
The mutated gene engineered by Jackson had created a transmissible prion disease that could not be attributed to any prions in the environment.
"One of the major tenets of the prion hypothesis is that a single amino acid change in PrP, associated with human disease, is sufficient to cause the spontaneous production of infectious material," says Lindquist, who is also a professor of biology at MIT and a Howard Hughes Medical Institute investigator. "Many people have tried and come close. But this is the first time it has been nailed."
This study was supported by the Department of Defense (DoD) and the National Institutes of Health (NIH).
Written by Nicole Giese
Susan Lindquist's primary affiliation is with Whitehead Institute for Biomedical Research, where her laboratory is located and all her research is conducted. She is also a Howard Hughes Medical Institute investigator and a professor of biology at Massachusetts Institute of Technology.
"Spontaneous generation of prion infectivity in fatal familial insomnia knock-in mice"
Neuron, August 27, 2009
Walker S. Jackson (1), Andrew Borkowski (1,2), Henryk Faas (3), Andrew Steele (1), Oliver King (1), Nicki Watson (1), Alan Jasanoff (3,4), and Susan Lindquist (1,2).1. Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142
4. Departments of Biological Engineering, Brain & Cognitive Sciences, and Nuclear Science & Engineering, Massachusetts Institute of Technology, 150 Albany St., NW14�, Cambridge, MA 02139
Nicole Giese | EurekAlert!
Multi-institutional collaboration uncovers how molecular machines assemble
02.12.2016 | Salk Institute
Fertilized egg cells trigger and monitor loss of sperm’s epigenetic memory
02.12.2016 | IMBA - Institut für Molekulare Biotechnologie der Österreichischen Akademie der Wissenschaften GmbH
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.
The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...
Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water
In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...
The efficiency of power electronic systems is not solely dependent on electrical efficiency but also on weight, for example, in mobile systems. When the weight of relevant components and devices in airplanes, for instance, is reduced, fuel savings can be achieved and correspondingly greenhouse gas emissions decreased. New materials and components based on gallium nitride (GaN) can help to reduce weight and increase the efficiency. With these new materials, power electronic switches can be operated at higher switching frequency, resulting in higher power density and lower material costs.
Researchers at the Fraunhofer Institute for Solar Energy Systems ISE together with partners have investigated how these materials can be used to make power...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
02.12.2016 | Medical Engineering
02.12.2016 | Agricultural and Forestry Science
02.12.2016 | Physics and Astronomy