Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Gene mutation alone causes transmissible prion disease

28.08.2009
For the first time, Whitehead Institute researchers have shown definitively that mutations associated with prion diseases are sufficient to cause a transmissible neurodegenerative disease.

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.

Full Citation:

"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
2. Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02142
3. Frances Bitter Magnet Laboratory, Massachusetts Institute of Technology, 166 Albany St., NW14, Cambridge, MA 02139

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!
Further information:
http://www.wi.mit.edu

More articles from Life Sciences:

nachricht How brains surrender to sleep
23.06.2017 | IMP - Forschungsinstitut für Molekulare Pathologie GmbH

nachricht A new technique isolates neuronal activity during memory consolidation
22.06.2017 | Spanish National Research Council (CSIC)

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Can we see monkeys from space? Emerging technologies to map biodiversity

An international team of scientists has proposed a new multi-disciplinary approach in which an array of new technologies will allow us to map biodiversity and the risks that wildlife is facing at the scale of whole landscapes. The findings are published in Nature Ecology and Evolution. This international research is led by the Kunming Institute of Zoology from China, University of East Anglia, University of Leicester and the Leibniz Institute for Zoo and Wildlife Research.

Using a combination of satellite and ground data, the team proposes that it is now possible to map biodiversity with an accuracy that has not been previously...

Im Focus: Climate satellite: Tracking methane with robust laser technology

Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.

Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...

Im Focus: How protons move through a fuel cell

Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.

As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...

Im Focus: A unique data centre for cosmological simulations

Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.

With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...

Im Focus: Scientists develop molecular thermometer for contactless measurement using infrared light

Temperature measurements possible even on the smallest scale / Molecular ruby for use in material sciences, biology, and medicine

Chemists at Johannes Gutenberg University Mainz (JGU) in cooperation with researchers of the German Federal Institute for Materials Research and Testing (BAM)...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Plants are networkers

19.06.2017 | Event News

Digital Survival Training for Executives

13.06.2017 | Event News

Global Learning Council Summit 2017

13.06.2017 | Event News

 
Latest News

Quantum thermometer or optical refrigerator?

23.06.2017 | Physics and Astronomy

A 100-year-old physics problem has been solved at EPFL

23.06.2017 | Physics and Astronomy

Equipping form with function

23.06.2017 | Information Technology

VideoLinks
B2B-VideoLinks
More VideoLinks >>>