Gene Mutation Alone Causes Transmissible Prion Disease

FINDINGS: Whitehead Institute researchers have shown definitively that mutations associated with prion diseases are sufficient to cause a transmissible neurodegenerative disease. 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.

RELEVANCE: Prions cause several diseases, including Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy (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.

Newswise — 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 encephalopathy (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).

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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.
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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., NW14–2213, Cambridge, MA 02139

역학조사 결과 인구 1백만명 당 1명씩의 비율로 산발적으로 발생하는 것으로 보고된 산발성 크로이츠펠트-야콥병(sCJD)처럼 광우병(BSE)의 경우도 몇몇 사례에서는 아주 드물게 유전자 돌연변이( genetic mutation )에 의해 발생할 수 있다는 연구결과가 발표되었습니다.

미국의 연구자들은 지난 2006년 Alabama주에서 발생한 광우병(BSE) 사례가 바로 이러한 사례에 해당된다고 밝히고 있습니다.

이러한 주장은 광우병이 자연발생적으로 발생할 수 있으며…결국 광우병을 완전히 박멸시키는 것은 불가능하다는 논리적 귀결에 도달하게 됩니다.(지난 해 국내에서는 5년내에 광우병이 지구상에서 영원히 사라질 것이라는 용감무쌍(?)한 주장도 나왔었는데… 유전자 돌연변이에 의한 자연발생적 광우병 발병 이론과 정면으로 충돌하네요.)

물론 산발성 크로이츠펠트-야콥병(sCJD)과 마찬가지로 산발성 광우병의 경우에도 변형 프리온에 의한 인체 전염은 가능하기 때문에… 사전예방적 원칙에 따라 광우병 위험물질의 철저한 제거 및 소각, 육골분 사료의 금지, 광우병 검사정책 등을 고려해야 할 것이라고 생각합니다.

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BSE Case Associated with Prion Protein Gene Mutation

Jürgen A. Richt^1¤*, S. Mark Hall²

1 National Animal Disease Center, United States Department of Agriculture, Agriculture Research Service, Ames, Iowa, United States of America, 2 National Veterinary Services Laboratories, Pathobiology Laboratory, Animal and Plant Health Inspection Service, United States Department of Agriculture, Ames, Iowa, United States of America

출처 : http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000156
          (전문 PDF 파일 첨부)

Abstract

Bovine spongiform encephalopathy (BSE) is a transmissible spongiform encephalopathy (TSE) of cattle and was first detected in 1986 in the United Kingdom. It is the most likely cause of variant Creutzfeldt-Jakob disease (CJD) in humans. The origin of BSE remains an enigma. Here we report an H-type BSE case associated with the novel mutation E211K within the prion protein gene (Prnp). Sequence analysis revealed that the animal with H-type BSE was heterozygous at Prnp nucleotides 631 through 633. An identical pathogenic mutation at the homologous codon position (E200K) in the human Prnp has been described as the most common cause of genetic CJD. This finding represents the first report of a confirmed case of BSE with a potential pathogenic mutation within the bovine Prnp gene. A recent epidemiological study revealed that the K211 allele was not detected in 6062 cattle from commercial beef processing plants and 42 cattle breeds, indicating an extremely low prevalence of the E211K variant (less than 1 in 2000) in cattle.

Author Summary

Bovine spongiform encephalopathy (BSE or Mad Cow Disease), a transmissible spongiform encephalopathy (TSE) or prion disease of cattle, was first discovered in the United Kingdom in 1986. BSE is most likely the cause of a human prion disease known as variant Creutzfeldt Jakob Disease (vCJD). In this study, we identified a novel mutation in the bovine prion protein gene (Prnp), called E211K, of a confirmed BSE positive cow from Alabama, United States of America. This mutation is identical to the E200K pathogenic mutation found in humans with a genetic form of CJD. This finding represents the first report of a confirmed case of BSE with a potential pathogenic mutation within the bovine Prnp gene. We hypothesize that the bovine Prnp E211K mutation most likely has caused BSE in “the approximately 10-year-old cow” carrying the E221K mutation.

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Gene mutation seen underlying some mad cow disease

출처 : 로이터통신 13/09/2008 11:12

By Maggie Fox, Health and Science Editor

WASHINGTON (Reuters) – A rare genetic mutation may underlie some cases of mad cow disease in cattle and its discovery may help shed light on where the epidemic started, U.S. researchers reported on Friday.

The mutation, in an Alabama cow that tested positive in 2006 for bovine spongiform encephalopathy, or BSE, is identical to one that causes a related brain-wasting disease in humans. This suggests BSE may sometimes arise spontaneously in cattle.

Jurgen Richt of Kansas State University said cattle producers must never let down their guard against BSE because cattle anywhere, at any time, can develop the disease.

The finding may support a 2005 theory that the BSE epidemic in cattle could be traced to feed contaminated with cattle remains from India, the researchers report in the Public Library of Science journal PLoS Pathogens.

BSE or mad cow disease swept through British dairy herds in the 1980s, forcing the destruction of millions of animals. No one ever found where it came from but most experts thought at the time it came from cattle feed that contained the remains of sheep infected with a similar disease called scrapie.

Cattle were never known to develop BSE before the epidemic, but some experts have argued they may have. This report lends credence to that idea.

and a human version called Creutzfeldt-Jakob disease, or CJD, are brain-destroying illnesses called transmissible spongiform encephalopathies. In some cases, animals or people that eat brain and nervous system material from victims of these diseases can develop them, too.

They are passed along by misfolded infectious protein fragments called prions.

’ANOTHER EPIDEMIC SOMEWHERE’

A very rare disease called variant CJD has been found in people who ate infected beef products. Fatal and incurable, it has affected just 167 people so far.

Most countries now ban the use of meat and other parts from mammals in food for cattle. They also ban the use of potentially infectious tissues such as brain and spinal cord in human food.

“There are tendencies around the world, now that the feed-borne epidemic has gone down, to relax these rules and regulations,” Richt said in a telephone interview.

“So if we have these genetic cases popping up here and there and we don’t have our mitigations in place, we will have another epidemic somewhere.”

He suggested breeding the gene out of cattle. “We can clean the world cattle herd of that mutation,” Richt said.

CJD is also known to pop up spontaneously in the human population. A genetic mutation causes the disease in one in a million people globally.

Richt and colleagues tested the brain of the Alabama cow and found a mutation identical to the prion gene mutation that causes some cases of CJD.

It is probably rare in cattle, found in fewer than one in 2,000, they said in the report, published at http://dx.plos.org/10.1371/journal.ppat.1000156.

But the animal passed along its mutation to its heifer, which suggests it is inherited.

(Editing by Xavier Briand)