Bax deletion does not protect neurons from BSE-induced death

Coulpier, Muriel; Messiaen, Sébastien; Hamel, Rodolphe; Marco, M. Fernández de; Lilin, Thomas; Éloit, Marc

doi:10.1016/j.nbd.2006.05.013

Cited by 32 publications

(25 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Misfolded monomers or oligomeric intermediates appear to be the more probable toxic species. This is consistent with recent data indicating that smaller subfibrillar particles with a mass equivalent to [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] PrP molecules are the most infectious moiety and may be much more toxic than larger amyloid fibrils or plaques [113].…”

Section: Prp In Aggresomessupporting

confidence: 93%

“…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.…”

Section: Loss Of Prpmentioning

confidence: 99%

See 1 more Smart Citation

Cellular pathogenesis in prion diseases

2008

View full text Add to dashboard Cite

-Prion diseases are characterised by neuronal loss, vacuolation (spongiosis), reactive astrocytosis, microgliosis and in most cases by the accumulation in the central nervous system of the abnormal prion protein, named PrP Sc . In this review on the "cellular pathogenesis in prion diseases", we have chosen to highlight the main mechanisms underlying the impact of PrP C /PrP Sc on neurons: the neuronal dysfunction, the neuronal cell death and its relation with PrP Sc accumulation, as well as the role of PrP Sc in the microglial and astrocytic reaction.

show abstract

Section: Prp In Aggresomessupporting

confidence: 93%

Section: Loss Of Prpmentioning

confidence: 99%

Cellular pathogenesis in prion diseases

2008

View full text Add to dashboard Cite

show abstract

“…It was recently reported that Bax deletion does not alter the clinical course, neuropathology, or PrP Sc accumulation seen in mice inoculated with a mouse-adapted strain of bovine spongiform encephalopathy (Coulpier et al, 2006). Thus, at least for this strain of prion, a Bax-dependent apoptotic pathway does not seem to play a major role in the neurotoxicity of PrP Sc .…”

Section: Scmentioning

confidence: 96%

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

Barmada

Roth

et al. 2007

J. Neurosci.

View full text Add to dashboard Cite

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.

show abstract

“…8,49 Consistent with the results reported here, several recent studies demonstrate that neuronal death in infectious prion diseases does not involve mitochondrially mediated apoptosis. 50,51 Most current strategies proposed for treatment of human prion diseases rely on inhibiting the formation of PrP Sc or enhancing its clearance. 52 Identification of the cell death pathways activated by pathogenic forms of PrP may allow design of a new class of therapeutics based on blocking prion-induced neurotoxic mechanisms rather than PrP Sc accumulation.…”

Section: Implications For Prion Diseasesmentioning

confidence: 99%

A Highly Toxic Cellular Prion Protein Induces a Novel, Nonapoptotic Form of Neuronal Death

Christensen

Dikranian

et al. 2010

The American Journal of Pathology

View full text Add to dashboard Cite

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.

show abstract

Bax deletion does not protect neurons from BSE-induced death

Cited by 32 publications

References 39 publications

Cellular pathogenesis in prion diseases

Cellular pathogenesis in prion diseases

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

A Highly Toxic Cellular Prion Protein Induces a Novel, Nonapoptotic Form of Neuronal Death

Contact Info

Product

Resources

About