미국 국립과학원회보(PNAS; Proceedings of National Academy of Science) 온라인판 최신호에 실린 스프립스 연구소(The Scripps Research Institute)의 과학자들의 프리온 연구 논문 초록입니다.

연구결과는 프리온은 DNA가 없음에도 불구하고 마치 바이러스처럼 돌연변이(Mutate)를 일으키고,  숙주의 환경에 적응(Adapt)할 수 있다는 것을 보여주고 있습니다.

이러한 연구결과는 2010년 1월 와이스만(Weissmann) 박사팀이 [사이언스]지에 발표했던 “프리온은 다윈의 진화를 할 수 있다”는 연구결과와 일맥상통하며, 비정형 프리온 단백질에 대한 가장 효과적인 치료제는 정상 프리온 단백질이 될 수 있다는 가능성을 열어 두었다고 볼 수 있습니다.

Transfer of a prion strain to different hosts leads to emergence of strain variants

Footnotes

• ¹To whom correspondence should be addressed. E-mail: charlesw@scripps.edu.


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  Author contributions: C.W. designed research; S.P.M., S.B., J.L., and I.S.-K. performed research; S.P.M., S.B., J.L., I.S.-K., and C.W. analyzed data; and S.P.M. and C.W. wrote the paper.



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  The authors declare no conflict of interest.



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  ↵*This Direct Submission article had a prearranged editor.



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  This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1013014108/-/DCSupplemental.

Epidemiological evidence of higher susceptibility to vCJD in the young

author email corresponding author email

BMC Infectious Diseases 2004, 4:26doi:10.1186/1471-2334-4-26

광우병, 인간광우병, 스크래피, 사슴 만성소모성질환(CWD) 등 전염성 해면상 뇌증(TSE)을 유발하는 병원성 프리온 단백질의 체내 이동경로와 병리기전을 연구한 논문입니다.


FEBS J. 2007 Feb;274(3):588-605.

The spread of prions through the body in naturally acquired transmissible spongiform encephalopathies.

Beekes M,

McBride PA.

Robert Koch-Institut (P24 – Transmissible Spongiforme Enzephalopathien), Berlin, Germany. BeekesM@rki.de

http://www.ncbi.nlm.nih.gov/pubmed/17288548

Abstract

Transmissible spongiform encephalopathies are fatal neurodegenerative diseases that are caused by unconventional pathogens and affect the central nervous system of animals and humans. Several different forms of these diseases result from natural infection (i.e. exposure to transmissible spongiform encephalopathy agents or prions, present in the natural environment of the respective host). This holds true also for scrapie in sheep, bovine spongiform encephalopathy in cattle, chronic wasting disease in elk and deer, or variant Creutzfeldt-Jakob disease in humans, all of which are assumed to originate predominantly from peroral prion infection. This article intends to provide an overview of the current state of knowledge on the spread of scrapie, chronic wasting disease, bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease agents through the body in naturally affected hosts, and in model animals experimentally challenged via the alimentary tract. Special attention is given to the tissue components and spreading pathways involved in the key stages of prion routing through the body, such as intestinal uptake, neuroinvasion of nerves and the central nervous system, and centrifugal spread from the brain and spinal cord to peripheral sites (e.g. sensory ganglia or muscles). The elucidation of the pathways and mechanisms by which prions invade a host and spread through the organism can contribute to efficient infection control strategies and the improvement of transmissible spongiform encephalopathy diagnostics. It may also help to identify prophylactic or therapeutic approaches that would impede naturally acquired transmissible spongiform encephalopathy infections.

콜린지 박사 등 영국의 연구자들이 프리온 단백질이 금속표면과 접촉시 CJD나 광우병을
유발하는 감염성 변형 프리온 단백질로 전환될 수 있다는 연구결과를 ‘포유류 프리온의
자연발생적 생성’이라는 제목으로 [미 국립과학원회보(PANS)] 최신호에 발표했습니다.

결과

1. 세포 배양을 통해 금속 표면에 자연발생적인 프리온 단백질 형성이 확실히 나타났다.

2. 적정(Titration)과 생쥐 생물학적 정량(Bioassay)을 통해 자연발생적 프리온의 감염성을
확인했다.

3. 자연발생적 프리온 단백질의 균주분류(Strain Typing)

전문 파일 : http://www.pnas.org/content/early/2010/07/16/1004036107.full.pdf+html

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Spontaneous generation of mammalian prions

 

Axonal prion protein is required for peripheral myelin maintenance

Juliane Bremer, Frank Baumann, Cinzia Tiberi, Carsten Wessig, Heike Fischer, Petra Schwarz, Andrew D Steele, Klaus V Toyka, Klaus-Armin Nave, Joachim Weis, et al.

출처 : Nature Neuroscience (24 January 2010) doi:10.1038/nn.2483 Article

연구팀의 연구결과는 [네이처 신경과학] 2010년 1월 24일자에 게재되었습니다.

이 기사에는 스위스 출신의 세계적인 프리온 연구의 권위자 아드리아노 아구치 박사의 20년에 걸친 프리온 연구에 대해서 간단하게 소개되어 있기도 합니다.

최근 과학자들은 프리온 단백질이 후각이나 시각과 관련이 있다는 연구결과를 발표한 바 있으며, 프리온 단백질이 알츠하이머병이 발생하지 않도록 보호해주는 기능을 한다는 연구결과 등을 발표하기도 했습니다.

=======================

Healthy prions protect nerves

Alison Abbott

출처 : Nature News (24 January 2010) doi:10.1038/news.2010.29 News
http://www.nature.com/news/2010/100124/full/news.2010.29.html

The proteins that can cause CJD have a vital role in the nervous system.

Alison Abbott

Prion proteins help to keep nerve cells well insulated.STEVE GSCHMEISSNER / SPL

After 20 years of research, scientists believe they have finally uncovered the normal function of prion proteins, which can cause deadly illnesses such as Creutzfeldt–Jakob disease (CJD) if they become incorrectly folded.

An international team of neuroscientists reports that, in mammals, the mysterious proteins help to maintain the myelin sheath that protects the body’s nerves.

“This opens a new door to studying some of the many common neuropathy disorders — which lead to weakness or loss of sensitivity of limbs — where we don’t know the cause,” says prion expert Simon Mead at University College London’s Institute of Neurology.

The authors suspect that their finding also applies to brain neurons. If so, this would have implications for treating deadly CJD and other transmissible spongiform encephalopathies. It could also offer a new way of looking at multiple sclerosis, an incurable disease caused by demyelination of nerves in the brain and spinal cord. The work is published online in Nature Neuroscience today¹.

Long search

Several functions have been proposed for prions during the past couple of decades, but none has survived close scrutiny.

“The first mouse with knocked-out prion genes was made back in 1991,” says Adriano Aguzzi at the University Hospital of Zurich in Switzerland, who led the new work. “We leapt on it, and studied it in every way we could think of — but never managed to find any obvious sign that lack of the prion was causing it harm.”

In fact, at first glance, lack of prions seemed like a good thing because it made mice immune to prion infection.

But four years ago, Aguzzi started to think again about a generally overlooked 1999 paper² by researchers in Japan that suggested the lack of prion protein caused the degeneration and demyelination of nerves outside the brain. He decided to undertake a thorough and systematic analysis of prions’ effects on such peripheral nerves.

Together with his colleagues, he studied four different strains of mice lacking the gene for the prion PrP^C. In every mouse they tested, regardless of strain, they found early evidence of myelin damage just six weeks after birth. By the age of two months, the nerves were extensively demyelinated, and the mice had become more sensitive to pain.

“Because there is no myelin damage at birth, we assumed prions are needed to maintain the quality of the myelin sheath, which diminishes throughout life,” says Aguzzi. Accordingly, when the researchers re-introduced prion proteins specifically into nerves, the demyelination did not occur. Curiously, however, only variants of prion proteins susceptible to cleavage by enzymes were effective.

But no variant of prion protein was able to prevent demyelination when introduced specifically into the Schwann cells that surround and support peripheral nerve cells. “This surprised us,” says Aguzzi, “since Schwann cells actually do the job of manufacturing fresh myelin.”

Aguzzi concludes that when nerves’ sheathes are suffering wear and tear, the nerves enzymatically cleave their prion proteins, releasing fragments that travel to Schwann cells, where they signal activation of myelin repair.

Brain effects

He also has a hunch, supported by preliminary data, that prion proteins will turn out to play the same part in supporting myelination in the brain. “So it is going to be interesting to see if prions play any role in demyelinating diseases that stem from the brain,” he says.

“Treatment of CJD targets prion proteins, which are assumed to be doing the damage,” says Mead. “But if CJD did indeed turn out to be caused by absence of prions, then we would have to rethink this therapeutic approach.”

Claude Carnaud, an immunologist working on prions at the INSERM research unit of the Pierre and Marie Curie University – Paris 6, says that some brain disorders that have been considered inflammatory in origin look like they may instead involve an absence of prions in the brain, at least in mice. “It will be very interesting to see if this also applies to multiple sclerosis,” he says. 

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  References

  
  
  
  
  1. Bremer, J. et al. Nature Neurosci. doi:10.1038/nn.2483 (2010).
     
  2. Nishida, N. et al. Lab. Invest. 79, 689-697 (1999).

=============================================

Prions ‘may keep nerves healthy’

Removing prion proteins led to a breakdown of the myelin sheath surrounding the nerve 출처 : BBC 00:02 GMT, Monday, 25 January 2010 http://news.bbc.co.uk/2/hi/health/8476093.stm Experiments on mice may help scientists understand the workings of the prion protein linked to brain disease vCJD. Swiss researchers say there is evidence that prions play a vital role in the maintenance of the sheath surrounding our nerves. They say it is possible that an absence of prions causes diseases of the peripheral nervous system. One expert said there was growing evidence that the prion had a number of important roles in the body. As well as the latest research in the journal Nature Neuroscience, other studies have indicated prions may protect us from Alzheimer’s disease or even play a role in our sense of smell. Most people started by focusing on prions in relation to a human disease, and have only recently started to examine what it normally does Professor Nigel Hooper, Leeds University The prion protein only came to the attention of scientists in recent years as they searched for the cause of vCJD – the human variant of BSE, or Mad Cow Disease. This degenerative and incurable brain condition is now thought to be caused by a “mis-folded” version of the prion. However, there is still little understanding of what the protein is supposed to do in its normal, healthy, form. Healthy prions The study, by scientists at the University Hospital in Zurich, looked at mice bred with fewer prion proteins. While these mice are known to be resistant to prion diseases equivalent to vCJD in humans, they showed a number of abnormalities, including a degeneration, later in life, of the peripheral nerve cells, and the protective myelin sheath which surrounds them. Peripheral nerves are those which link the limbs and organs to the central nervous system – the spinal cord and brain. Looking more closely, researchers examined the effects of removing the prion protein in both the nerve cells themselves, and the Schwann cells surrounding them, which are responsible for making the myelin sheath. While removing protein from the Schwann cells had no effect, taking it from the neurons led to a breakdown of the myelin and degeneration of the nerve cells. They said that the knowledge that prion protein played some role in the healthy upkeep of nerve cells could offer a new avenue of research into diseases affecting humans. However, scientists caution that it is too early to pick out a particular peripheral nerve condition which might correspond to the mouse experiments. Recent work Professor Nigel Hooper, from the University of Leeds, agreed that the role of the protein was not well understood. His own work, published in 2007, suggested that it might offer some protection from the development of Alzheimer’s disease. But he said this was unlikely to be the complete answer. He said: “Most people started by focusing on prions in relation to a human disease, and have only recently started to examine what it normally does. “There is some evidence that it could have a number of different roles, depending on its whereabouts in the body – a recent paper linked it to olfaction or the sense of smell.”

Gerold Schmitt-Ulms^1,2*, Sepehr Ehsani^1,2, Joel C. Watts^1,2,3, David Westaway⁵, Holger Wille^3,4

1 Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada, 2 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada, 3 Institute for Neurodegenerative Diseases, University of California San Francisco, San Francisco, California, United States of America, 4 Department of Neurology, University of California San Francisco, San Francisco, California, United States of America, 5 Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, Canada

In the more than twenty years since its discovery, both the phylogenetic origin and cellular function of the prion protein (PrP) have remained enigmatic. Insights into a possible function of PrP may be obtained through the characterization of its molecular neighborhood in cells. Quantitative interactome data demonstrated the spatial proximity of two metal ion transporters of the ZIP family, ZIP6 and ZIP10, to mammalian prion proteins in vivo. A subsequent bioinformatic analysis revealed the unexpected presence of a PrP-like amino acid sequence within the N-terminal, extracellular domain of a distinct sub-branch of the ZIP protein family that includes ZIP5, ZIP6 and ZIP10. Additional structural threading and orthologous sequence alignment analyses argued that the prion gene family is phylogenetically derived from a ZIP-like ancestral molecule. The level of sequence homology and the presence of prion protein genes in most chordate species place the split from the ZIP-like ancestor gene at the base of the chordate lineage. This relationship explains structural and functional features found within mammalian prion proteins as elements of an ancient involvement in the transmembrane transport of divalent cations. The phylogenetic and spatial connection to ZIP proteins is expected to open new avenues of research to elucidate the biology of the prion protein in health and disease.

Diseased prion proteins are responsible for the fatal neurodegenerative Creutzfeldt-Jakob disease (CJD) in humans, and BSE, scrapie and chronic wasting disease (CWD) in livestock. Overall, this work holds promise for efforts to reveal the physiological function of members of the prion protein family and may provide insights into the origins and underlying constraints of the conformational changes associated with prion diseases. The study was published on September 28, 2009, in the online journal PLoS ONE.

Principal investigator Gerold Schmitt-Ulms (Centre for Research in Neurodegenerative Diseases; Department of Laboratory Medicine and Pathobiology, U of T) and his graduate student Sepehr Ehsani teamed up with Holger Wille and Joel Watts (University of California, San Francisco) and David Westaway (University of Alberta) for this project. “The prion protein was discovered over twenty years ago and has been studied intensively. Nobody, however, knew its evolutionary origin and much confusion surrounds its physiological function,” says Prof. Schmitt-Ulms. The team’s analysis suggests that the prion gene is descended from the more ancient ZIP family of metal ion transporters. Members of the ZIP protein family are well known for their ability to transport zinc and other metals across cell membranes.

The U of T laboratory initially demonstrated the physical proximity of two metal ion transporters, ZIP6 and ZIP10, to mammalian prion proteins in living cells. As with the normal cellular prion protein, ZIP6 and ZIP10 exhibit widespread expression in biological tissues with high transcript levels in the brain. Schmitt-Ulms then made the startling discovery that prion and ZIP proteins contain extensive stretches of similar amino acid sequence. The researchers next documented that the respective segments within ZIP and prion proteins are computationally predicted to acquire a highly similar three-dimensional structure. Finally, the team uncovered multiple additional commonalities between ZIP and prion proteins which led them to conclude these molecules are evolutionarily related.

Most proteins do not act in isolation but partner with other proteins to exert their biological roles. The relationship between ZIP-family and prion proteins may thus provide a new angle from which to study the biology of the prion protein in health and disease. The level of shared characteristics between these protein families, in addition to the presence of prion protein genes in most chordate (i.e., backboned) species, place the split from the ZIP-like ancestor gene at the base of the chordate lineage.

Although no single evidence firmly established the phylogenetic relationship between ZIP and prion genes, Schmitt-Ulms is confident that the many corroborating pieces of evidence collected and, equally important, the absence of any conflicting observations, allow no other conclusion to be drawn.

This project was funded with support from the Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, Alberta Heritage Foundation for Medical Research, National Institutes of Health and W. Garfield Weston Foundation.

Journal reference:

1. Gerold Schmitt-Ulms, Sepehr Ehsani, Joel C. Watts, David Westaway, Holger Wille. Evolutionary Descent of Prion Genes from the ZIP Family of Metal Ion Transporters. PLoS ONE, September 28, 2009 DOI: 10.1371/journal.pone.0007208