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From: TSS ()
Subject: Anchorless Prion Protein Results in Infectious Amyloid Disease Without Clinical Scrapie
Date: June 2, 2005 at 6:38 pm PST

[DOI: 10.1126/science.1110837]
Research Articles
Anchorless Prion Protein Results in Infectious Amyloid Disease Without Clinical Scrapie
Bruce Chesebro,1* Matthew Trifilo,2 Richard Race,1 Kimberly Meade-White,1 Chao Teng,2 Rachel LaCasse,1 Lynne Raymond,1 Cynthia Favara,1 Gerald Baron,1 Suzette Priola,1 Byron Caughey,1 Eliezer Masliah,3 Michael Oldstone2
In prion and Alzheimer's diseases, the roles played by amyloid versus nonamyloid deposits in brain damage remain unresolved. In scrapie-infected transgenic mice expressing prion protein (PrP) lacking the glycosylphosphatidylinositol (GPI) membrane anchor, abnormal protease-resistant PrPres was deposited as amyloid plaques, rather than the usual nonamyloid form of PrPres. Although PrPres amyloid plaques induced brain damage reminiscent of Alzheimer's disease, clinical manifestations were minimal. In contrast, combined expression of anchorless and wild-type PrP produced accelerated clinical scrapie. Thus, the PrP GPI anchor may play a role in the pathogenesis of prion diseases.

1 Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, MT 59840, USA.
2 Division of Virology, Department of Neuropharmacology, Scripps Research Institute, La Jolla, CA 92037, USA.
3 Departments of Neurosciences and Pathology, University of California, San Diego, La Jolla, CA 92093, USA.

* To whom correspondence should be addressed. E-mail: bchesebro@niaid.nih.gov


http://www.sciencemag.org/cgi/content/short/308/5727/1435


Anchors and Amyloid Effects
It is not known whether amyloid deposited in the brain during protein misfolding diseases such as prion diseases and Alzheimer's disease is directly responsible for the neurotoxicity associated with these neurodegenerative syndromes. Chesebro et al. (p. 1435; see the Perspective by Aguzzi) describe scrapie infection experiments using transgenic mice expressing glycosylphosphatidylinositol (GPI)- negative prion protein (PrP), which is secreted from the cells where it is produced. Although the scrapie agent infected these mice and disease-associated protease-resis-tant prion protein (PrP-res) was produced, no clinical disease was detected during an observation period of more than 600 days. Lack of clinical disease correlated with PrP-res deposited in brain as amyloid plaques rather than as the diffuse PrP-res usually seen in mouse scrapie and human sporadic Creutzfeldt-Jakob disease, and the neuropathology at the ultrastructural level was similar to that of Alzheimer's disease. These marked differences in brain pathogenic effects of amyloid versus nonamyloid PrP-res suggest that amyloid PrP-res is actually less toxic than nonamyloid PrP-res. Furthermore, the PrP GPI anchor influences the pathogenic effects of scrapie infection and amyloid generation in vivo during prion disease.
CREDIT: CHESEBRO ET AL.


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[DOI: 10.1126/science.1114168]
Perspectives
CELL BIOLOGY:
Prion Toxicity: All Sail and No Anchor
Adriano Aguzzi
Cellular prion proteins are converted into an aggregated, neurotoxic form when cells are attacked by infectious prion particles. In his Perspective, Aguzzi discusses new insights into prion disease progression. Genetically altered mice that express a secreted form of prion protein never succumb to disease, even though prion aggregates form in their brains.


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The author is at the Institute of Neuropathology, University Hospital of Zürich, CH-8091 Zürich, Switzerland. E-mail: adriano@pathol.unizh.ch

http://www.sciencemag.org/cgi/content/short/308/5727/1420

TSS



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