title: 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 PrPdelta32-134 and PrPdelta105-125, 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(PrPdelta32-134) 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(delta105-125) mice. Our results indicate that Bax-related pathways mediate the initial neurotoxic actions of PrPdelta32-134 but that neurodegeneration induced by this protein as well as by PrPdelta105-125 also involves Bax-independent pathways.
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Aimin
authors.initials: A
authors.lastname: Li
authors.forename: Sami J
authors.initials: SJ
authors.lastname: Barmada
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Roth
authors.forename: David A
authors.initials: DA
authors.lastname: Harris
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D009434:Neural Pathways / Q000378:metabolism* / Q000503:physiopathology; D011328:Prions / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D017384:Sequence Deletion; D051028:bcl-2-Associated X Protein / Q000172:deficiency / Q000235:genetics* / Q000502:physiology
chemical_list: D011328:Prions; D051028:bcl-2-Associated X Protein