title: Functionally relevant domains of the prion protein identified in vivo.
abstract: The prion consists essentially of PrP(Sc), a misfolded and aggregated conformer of the cellular protein PrP(C). Whereas PrP(C) deficient mice are clinically healthy, expression of PrP(C) variants lacking its central domain (PrP(DeltaCD)), or of the PrP-related protein Dpl, induces lethal neurodegenerative syndromes which are repressed by full-length PrP. Here we tested the structural basis of these syndromes by grafting the amino terminus of PrP(C) (residues 1-134), or its central domain (residues 90-134), onto Dpl. Further, we constructed a soluble variant of the neurotoxic PrP(DeltaCD) mutant that lacks its glycosyl phosphatidyl inositol (GPI) membrane anchor. Each of these modifications abrogated the pathogenicity of Dpl and PrP(DeltaCD) in transgenic mice. The PrP-Dpl chimeric molecules, but not anchorless PrP(DeltaCD), ameliorated the disease of mice expressing truncated PrP variants. We conclude that the amino proximal domain of PrP exerts a neurotrophic effect even when grafted onto a distantly related protein, and that GPI-linked membrane anchoring is necessary for both beneficial and deleterious effects of PrP and its variants.
authors.affiliation: Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Frank
authors.initials: F
authors.lastname: Baumann
authors.forename: Jens
authors.initials: J
authors.lastname: Pahnke
authors.forename: Ivan
authors.initials: I
authors.lastname: Radovanovic
authors.forename: Thomas
authors.initials: T
authors.lastname: Rülicke
authors.forename: Juliane
authors.initials: J
authors.lastname: Bremer
authors.forename: Markus
authors.initials: M
authors.lastname: Tolnay
authors.forename: Adriano
authors.initials: A
authors.lastname: Aguzzi
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D014644:Genetic Variation; D017261:Glycosylphosphatidylinositols / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism; D009498:Neurotoxins / Q000737:chemistry; D010641:Phenotype; D000072002:Prion Proteins; D011328:Prions / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D015398:Signal Transduction; D019076:Transgenes
chemical_list: D017261:Glycosylphosphatidylinositols; D009498:Neurotoxins; D000072002:Prion Proteins; D011328:Prions; C512657:Prnp protein, mouse; D011993:Recombinant Fusion Proteins