Document Detail

Neurodegenerative illness in transgenic mice expressing a transmembrane form of the prion protein.
MedLine Citation:
PMID:  15800202     Owner:  NLM     Status:  MEDLINE    
Although PrP(Sc) is thought to be the infectious form of the prion protein, it may not be the form that is responsible for neuronal cell death in prion diseases. (Ctm)PrP is a transmembrane version of the prion protein that has been proposed to be a neurotoxic intermediate underlying prion-induced pathogenesis. To investigate this hypothesis, we have constructed transgenic mice that express L9R-3AV PrP, a mutant prion protein that is synthesized exclusively in the (Ctm)PrP form in transfected cells. These mice develop a fatal neurological illness characterized by ataxia and marked neuronal loss in the cerebellum and hippocampus. (Ctm)PrP in neurons cultured from transgenic mice is localized to the Golgi apparatus, rather than to the endoplasmic reticulum as in transfected cell lines. Surprisingly, development of the neurodegenerative phenotype is strongly dependent on coexpression of endogenous, wild-type PrP. Our results provide new insights into the cell biology of (Ctm)PrP, the mechanism by which it induces neurodegeneration, and possible cellular activities of PrP(C).
Richard S Stewart; Pedro Piccardo; Bernardino Ghetti; David A Harris
Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of neuroscience : the official journal of the Society for Neuroscience     Volume:  25     ISSN:  1529-2401     ISO Abbreviation:  J. Neurosci.     Publication Date:  2005 Mar 
Date Detail:
Created Date:  2005-03-31     Completed Date:  2006-03-23     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  8102140     Medline TA:  J Neurosci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3469-77     Citation Subset:  IM    
Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
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MeSH Terms
Animals, Newborn
Arginine / genetics
Blotting, Western / methods
Brain / metabolism,  pathology
Cells, Cultured
Cerebellum / cytology
Detergents / pharmacology
Disease Models, Animal
Electrophoresis, Polyacrylamide Gel / methods
Fluorescent Antibody Technique / methods
Gene Expression
Glial Fibrillary Acidic Protein / metabolism
Golgi Apparatus / metabolism
Immunoprecipitation / methods
Leucine / genetics
Membrane Proteins / metabolism
Methionine / pharmacokinetics
Mice, Inbred C57BL
Mice, Transgenic
Neurodegenerative Diseases / genetics,  metabolism*,  physiopathology
Octoxynol / pharmacology
PrPSc Proteins / genetics,  metabolism*
Prion Diseases / genetics,  metabolism*,  physiopathology
Protein Structure, Tertiary / genetics,  physiology*
RNA, Messenger / metabolism
Reverse Transcriptase Polymerase Chain Reaction / methods
Sulfur Isotopes / pharmacokinetics
Time Factors
Type C Phospholipases / pharmacology
Valine / genetics
Grant Support
Reg. No./Substance:
0/Detergents; 0/Glial Fibrillary Acidic Protein; 0/Membrane Proteins; 0/PrPSc Proteins; 0/RNA, Messenger; 0/Sulfur Isotopes; 0/macrogolgin; 61-90-5/Leucine; 63-68-3/Methionine; 7004-03-7/Valine; 74-79-3/Arginine; 9002-93-1/Octoxynol; EC 3.1.4.-/Type C Phospholipases

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