사람에서 가장 일반적인 유전적 CJD의 원인으로 알려진 프리온 단백질 유전자의 E200K 부위에서 특징적인 병원성 돌연변이에서 amyloid β(Aβ) plaques가 축적된다는 사실을 최초로 보고한 논문입니다.

[ Arch Neurol] 2009년 10월호에 실렸는데요…  프리온 유전자 200번 코돈의 E/K 이형성과 129번 코돈의 MM 동질접합체를 가진 가족성 CJD(Familial Creutzfeldt-Jakob Disease)의 뇌를 부검한 결과 베타 아밀로이드반(amyloid β plaques)가 축적된다는 사실을 확인함으로써 CJD와 알츠하이머병이 서로 연관이 있을 수 있다는 주장에 힘을 실어준 연구라고 해석할 수 있습니다.

앞으로 후속 연구가 더 이루어지면 크로이츠펠트-야콥병과 알츠하이머병의 연관관계에 대한 규명을 좀 더 분명하게 알 수 있으리라 생각합니다.

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

Codistribution of Amyloid β Plaques and Spongiform Degeneration in Familial Creutzfeldt-Jakob Disease With the E200K-129M Haplotype

Nupur Ghoshal, MD, PhD; Ignazio Cali, MS; Richard Justin Perrin, MD, PhD; S. Andrew Josephson, MD; Ning Sun, MD, PhD; Pierluigi Gambetti, MD; John Carl Morris, MD

출처 : Arch Neurol. 2009;66(10):1240-1246.
http://archneur.ama-assn.org/cgi/content/abstract/66/10/1240?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=Ghoshal+N&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT

Background  Dominantly inherited Creutzfeldt-Jakob disease (CJD) represents 5% to 15% of all CJD cases. The E200K mutation in the prion protein (PrP) gene (PRNP) is the most frequent cause of familial CJD. Coexistent amyloid β (Aβ) plaques have been reported in some transmissible spongiform encephalopathies but to date have not been reported in familial CJD with the E200K mutation.

Objective  To characterize a family with CJD in which Aβ plaques codistribute with spongiform degeneration.

Design  Clinicopathologic and molecular study of a family with CJD with the E200K-129M haplotype.

Setting  Alzheimer disease research center.

Participants  Two generations of a family.

Main Outcome Measures  Clinical, biochemical, and neuropathologic observations in 2 generations of a family.

Results  In this kindred, 3 autopsied cases showed pathologic changes typical for the E200K-129M haplotype, including spongiform degeneration, gliosis, neuronal loss, and PrP deposition. Moreover, 2 of these cases (ages 57 and 63 years) showed numerous Aβ plaques codistributed with spongiform degeneration. APOE genotyping in 2 cases revealed that Aβ plaques were present in the APOE 4 carrier but not in the APOE 4 noncarrier. Two additional cases exhibited incomplete penetrance, as they had no clinical evidence of CJD at death after age 80 years but had affected siblings and children.

Conclusions  To our knowledge, this is the first description of Aβ plaques in familial CJD with the E200K mutation. The codistribution of plaques and CJD-associated changes suggests that PrP plays a central role in Aβ formation and that Aβ pathology and prion disease likely in fluence each other. The kindred described herein provides support that PrPE200K may result in increased Aβ deposition.

Author Affiliations: Department of Neurology and Alzheimer’s Disease Research Center (Drs Ghoshal, Perrin, and Morris) and Division of Neuropathology, Department of Pathology and Immunology (Drs Perrin and Morris), Washington University School of Medicine, St Louis, Missouri; National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, Ohio (Mr Cali and Dr Gambetti); Department of Neurology, University of California, San Francisco (Dr Josephson); and DuPage Neurological Associates, Willowbrook, Illinois (Dr Sun).

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

Family’s inherited condition links prion diseases, Alzheimer’s

December 9, 2009 By Michael Purdy
www.physorg.com/news179570626.html

(PhysOrg.com) — A laboratory connection between Alzheimer’s disease and brain-wasting diseases such as the human form of mad cow disease has moved into the clinic for what is believed to be the first time, manifesting itself in the brains of patients with a rare inherited disorder.

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).

* * *
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., NW14–2213, Cambridge, MA 02139