N-Terminally Deleted Forms of the Prion Protein Activate Both Bax-Dependent and Bax-Independent Neurotoxic Pathways

Abstract

Transgenic (Tg) mice expressing prion protein (PrP) with a deletion of the flexible, N-terminal tail encompassing residues 32-134 spontaneously develop ataxia, degeneration of cerebellar granule cells, and vacuolation of white matter in the brain and spinal cord, resulting in death by 3 months of age. These abnormalities are completely abrogated by coexpression of wild-type PrP from a single copy of the endogenous Prn-p gene. A similar but much more severe phenotype is seen in transgenic mice expressing PrP deleted for a conserved block of 21 amino acids (residues 105-125) within the N-terminal tail. The latter animals die within 1 week of birth in the absence of endogenous PrP, and fivefold overexpression of wild-type PrP is required to delay death beyond 1 year. To define the cellular pathways mediating the neurotoxicity of PrP⌬32-134 and PrP⌬105-125, we analyzed the effect of genetically deleting the proapoptotic protein Bax in mice expressing these neurotoxic forms of PrP. We find that Bax deletion in Tg(PrP⌬32-134) mice delays the development of clinical illness and slows apoptosis of cerebellar granule cells but has no effect on white matter degeneration. In contrast, Bax deletion has no effect on the clinical or neuropathological phenotype of Tg(⌬105-125) mice. Our results indicate that Bax-related pathways mediate the initial neurotoxic actions of PrP⌬32-134 but that neurodegeneration induced by this protein as well as by PrP⌬105-125 also involves Bax-independent pathways.

Prion Neurotoxicity: Insights from Prion Protein Mutants

“…By electron microscopy, granule cells display a unique, non-apoptotic ultrastructural morphology (Christensen et al, manuscript in preparation). In conjunction with evidence that neurodegeneration in Tg(ΔCR) mice is Bax-independent (Li et al, 2007a), our ultrastructural and biochemical data indicate that PrPΔCR is activating a novel form of neuronal death that is not related to apoptosis, necrosis, or autophagy.…”

New insights into cellular prion protein (PrPc) functions: The “ying and yang” of a relevant protein

“…Consequently, four studies have recently reported that cell death in N-terminal truncated overpressing mice and in the Nagasaki line is regulated in a Bcl-2/BAX manner (Heitz et al, 2008;Heitz et al, 2007;Li et al, 2007a;Nicolas et al, 2007) (see Table 1). Surprisingly, contradictory results have been obtained in the latter strain, regarding the contribution of BAX depletion to ataxic syndrome rescue (Dong et al, 2007;Heitz et al, 2007).…”

Cellular pathogenesis in prion diseases

“…As the Bax pro-apoptotic pathway seems to be implicated in neuronal death, as shown by Chiesa et al in the inherited prion disease transgenic mouse model Tg(PG14) [20,67], it is therefore tempting to propose that loss of this function will be a determinant for neuronal cell death. However, the Bax pathway is not an obligatory phenomenon [67] since in another study Coulpier et al have reported that Bax −/− mice challenged with the BSE (Bovine spongiform encephalopathy) agent developed an unaltered prion disease in terms of neuronal loss [26]. To reconcile these data, a third study using transgenic mice showed that N-terminally deleted forms of the prion protein activated both Baxdependent and Bax-independent neurotoxic pathways.…”

“…To reconcile these data, a third study using transgenic mice showed that N-terminally deleted forms of the prion protein activated both Baxdependent and Bax-independent neurotoxic pathways. Bax deletion in Tg(PrPΔ32-134) mice delayed the development of clinical illness and slowed apoptosis of cerebellar granule cells but had no effect on white matter degeneration [67]. Bax deletion had also no effect in Tg(PrPΔ105-125) mice [67] suggesting that the PrP deleted domains are important for the interaction with Bax cell-death signalling molecules.…”

“…Bax deletion in Tg(PrPΔ32-134) mice delayed the development of clinical illness and slowed apoptosis of cerebellar granule cells but had no effect on white matter degeneration [67]. Bax deletion had also no effect in Tg(PrPΔ105-125) mice [67] suggesting that the PrP deleted domains are important for the interaction with Bax cell-death signalling molecules. Altogether these studies suggest the existence of multiple molecular death pathways in prion diseases and that specific domains of PrP are essential for its neuroprotective activity.…”