Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 176, Issue 6, Pages 2695-2706Publisher
ELSEVIER SCIENCE INC
DOI: 10.2353/ajpath.2010.091007
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Funding
- National Institutes of Health [HD 37100, NS035107, N5057098, NS052526, NS040975, NS04691003]
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Several different deletions within the N-terminal tail of the prion protein (PrP) induce massive neuronal death when expressed in transgenic mice. This toxicity is dose-dependently suppressed by coexpression of full-length PrP, suggesting that it results from subversion of a normal physiological activity of cellular PrP. We performed a combined biochemical and morphological analysis of Tg(Delta CR) mice, which express PrP carrying a 21-aa deletion (residues 105-125) within a highly conserved region of the protein. Death of cerebellar granule neurons in Tg(Delta CR) mice is not accompanied by activation of either caspase-3 or caspase-8 or by increased levels of the autophagy marker, LC3-II. In electron micrographs, degenerating granule neurons displayed a unique morphology characterized by heterogeneous condensation of the nuclear matrix without formation of discrete chromatin masses typical of neuronal apoptosis. Our data demonstrate that perturbations in PrP functional activity induce a novel, nonapoptotic, nonautophagic form of neuronal death whose morphological features are reminiscent of those associated with excitotoxic stress. (Am J Pathol 2010, 176:2695-2706; DOI: 10.2353/ajpath.2010.091007)
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