title: A highly toxic cellular prion protein induces a novel, nonapoptotic form of neuronal death.
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(DeltaCR) 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(DeltaCR) 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.
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Christensen
authors.forename: Krikor
authors.initials: K
authors.lastname: Dikranian
authors.forename: Aimin
authors.initials: A
authors.lastname: Li
authors.forename: Kathleen C
authors.initials: KC
authors.lastname: Baysac
authors.forename: Ken C
authors.initials: KC
authors.lastname: Walls
authors.forename: John W
authors.initials: JW
authors.lastname: Olney
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Roth
authors.forename: David A
authors.initials: DA
authors.lastname: Harris
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001343:Autophagy / Q000502:physiology; D015415:Biomarkers / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D016923:Cell Death / Q000502:physiology*; D048430:Cell Shape; D002531:Cerebellum / Q000166:cytology*; D004789:Enzyme Activation; D051379:Mice; D008808:Mice, Inbred CBA; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D009474:Neurons / Q000473:pathology / Q000502:physiology* / Q000648:ultrastructure; D018621:PrPC Proteins / Q000235:genetics / Q000633:toxicity*; D011328:Prions / Q000235:genetics / Q000378:metabolism
chemical_list: D015415:Biomarkers; D018621:PrPC Proteins; D011328:Prions; D053148:Caspase 3; D053181:Caspase 8
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