title: Lethal recessive myelin toxicity of prion protein lacking its central domain.
abstract: PrP(C)-deficient mice expressing prion protein variants with large amino-proximal deletions (termed PrP(DeltaF)) suffer from neurodegeneration, which is rescued by full-length PrP(C). We now report that expression of PrP(DeltaCD), a PrP variant lacking 40 central residues (94-134), induces a rapidly progressive, lethal phenotype with extensive central and peripheral myelin degeneration. This phenotype was rescued dose-dependently by coexpression of full-length PrP(C) or PrP(C) lacking all octarepeats. Expression of a PrP(C) variant lacking eight residues (114-121) was innocuous in the presence or absence of full-length PrP(C), yet enhanced the toxicity of PrP(DeltaCD) and diminished that of PrP(DeltaF). Therefore, deletion of the entire central domain generates a strong recessive-negative mutant of PrP(C), whereas removal of residues 114-121 creates a partial agonist with context-dependent action. These findings suggest that myelin integrity is maintained by a constitutively active neurotrophic protein complex involving PrP(C), whose effector domain encompasses residues 94-134.
authors.affiliation: Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Frank
authors.initials: F
authors.lastname: Baumann
authors.forename: Markus
authors.initials: M
authors.lastname: Tolnay
authors.forename: Christine
authors.initials: C
authors.lastname: Brabeck
authors.forename: Jens
authors.initials: J
authors.lastname: Pahnke
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kloz
authors.forename: Hartmut H
authors.initials: HH
authors.lastname: Niemann
authors.forename: Mathias
authors.initials: M
authors.lastname: Heikenwalder
authors.forename: Thomas
authors.initials: T
authors.lastname: Rülicke
authors.forename: Alexander
authors.initials: A
authors.lastname: Bürkle
authors.forename: Adriano
authors.initials: A
authors.lastname: Aguzzi
mesh_terms: D000818:Animals; D017353:Gene Deletion; D005804:Genes, Lethal; D005808:Genes, Recessive; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D008954:Models, Biological; D050505:Mutant Proteins / Q000502:physiology; D009186:Myelin Sheath / Q000378:metabolism*; D018621:PrPC Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D017434:Protein Structure, Tertiary; D016019:Survival Analysis
chemical_list: D050505:Mutant Proteins; D018621:PrPC Proteins