help button home button Am J Pathol Epitomics, Inc.
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Originally published online as doi:10.2353/ajpath.2009.090125 on August 21, 2009

Published online before print August 21, 2009
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
ajpath.2009.090125v1
175/3/1208    most recent
Right arrow Purchase Article
Right arrow View Shopping Cart
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Google Scholar
Right arrow Articles by Jeffrey, M.
Right arrow Articles by Harris, D. A.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Jeffrey, M.
Right arrow Articles by Harris, D. A.
(American Journal of Pathology. 2009;175:1208-1217.)
© 2009 American Society for Investigative Pathology and Crown Copyright 2009
DOI: 10.2353/ajpath.2009.090125

Prion Protein with an Insertional Mutation Accumulates on Axonal and Dendritic Plasmalemma and Is Associated with Distinctive Ultrastructural Changes

Martin Jeffrey*, Caroline Goodsir*, Gillian McGovern*, Sami J. Barmada{dagger}, Andrea Z. Medrano{dagger} and David A. Harris{dagger}

From the Veterinary Laboratories Agency,* Lasswade Laboratory, Pentlands Science Park, Bush Loan, Penicuik, Midlothian, Scotland; and the Department of Cell Biology and Physiology,{dagger} Washington University School of Medicine, St. Louis, Missouri

Prion diseases are fatal neurological diseases characterized by central nervous system deposition of abnormal forms of a membrane glycoprotein designated PrP (prion protein). Tg(PG14) transgenic mice express PrP that harbor a nine-octapeptide insertional mutation homologous to one described in a familial prion disease of humans. Tg(PG14) mice spontaneously develop a fatal neurological illness accompanied by massive apoptosis of cerebellar granule neurons and accumulation of an aggregated and weakly protease-resistant form of PrP that is not infectious. Previous light microscopic analyses of these mice left open questions regarding the subcellular distribution of the mutant protein and the nature of the neuropathological lesions produced. To address these questions, we undertook an immunogold electron microscopic study of Tg(PG14) mice. We found that mutant PrP is localized primarily on the plasma membrane of dendrites and unmyelinated axons in the hippocampus and cerebellum, with little labeling of either neuronal cell bodies or intracellular organelles. PrP deposits were shown to be associated with degenerative changes in dendritic structure. We also describe for the first time marked pathology in myelinated axons, and alterations in the axon/oligodendrocyte interface. Taken together, our results suggest cellular mechanisms by which mutant PrPs produce pathology. In addition, they highlight distinctions between familial and infectious prion disorders at the ultrastructural level that correlate with differences in cellular trafficking of the disease-associated PrP forms.






HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Copyright © 2009 by the American Society for Investigative Pathology.