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(⌬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(⌬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.

Cell death and neurodegeneration in the postnatal development of cerebellar vermis in normal and Reeler mice

“…For example, contrasting results were obtained after ischemia or stroke in several mammalian species, as mixed apoptotic/necrotic figures were described in rat (Wei et al, 2006) or mouse (Pamenter et al, 2012), whereas no evidence of apoptosis was described in gerbils (Colbourne et al, 1999), and apoptosis and necrosis occurred in separate neuronal populations in dogs (Martin et al, 2000). Likewise, death in prionic infection was reported to be autophagic by some authors (Liberski et al, 2008) but others denied the occurrence of autophagy and, instead, described a novel, non-apoptotic, non-autophagic form of neuronal death in a transgenic mouse model (Christensen et al, 2010). Finally, a cross-talk between neuronal apoptosis and autophagy was described in a mouse model of Alzheimer's disease, highlighting the concept that such an interaction had important consequences in the ultimate survival of neurons in the course of neurodegeneration (Yang et al, 2008).…”

Neurotoxic Mutants of the Prion Protein Induce Spontaneous Ionic Currents in Cultured Cells

“…We have found that cerebellar granule cells in Tg(⌬CR) mice die by a novel, non-apoptotic pathway that is reminiscent of certain forms of glutamate-induced cell death (43). This suggests that ⌬CR PrP-induced currents may initiate or augment excitotoxic pathways in the cerebellum.…”

Ion channels induced by the prion protein

“…Consistent with this suggestion, we have found that granule cell neurons in Tg(ΔCR) mice degenerate by a distinctive, non-apoptotic mechanism that bears similarities to the pathways associated with glutamate-induced excitotoxicity. 33 Moreover, neurons expressing ΔCR PrP are more sensitive to the excitotoxic effects of exogenously applied glutamate (unpublished data). WT PrP rescues ΔCR PrP toxicity in a dose dependent manner, which might be explained by a homo-oligomerization process in which increasing proportions of WT PrP subunits dampen the effects of ΔCR PrP (Fig.…”