A highly toxic cellular prion protein induces a novel, nonapoptotic form of neuronal death

Heather M. Christensen, Krikor Dikranian, Aimin Li, Kathleen C. Baysac, Ken C. Walls, John W. Olney, Kevin A. Roth, David A. Harris

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

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(ΔCR) 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(ΔCR) 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.

Original languageEnglish
Pages (from-to)2695-2706
Number of pages12
JournalAmerican Journal of Pathology
Volume176
Issue number6
DOIs
StatePublished - Jun 2010

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