title: Truncated prion protein and Doppel are myelinotoxic in the absence of oligodendrocytic PrPC.
abstract: The cellular prion protein PrP(C) confers susceptibility to transmissible spongiform encephalopathies, yet its normal function is unknown. Although PrP(C)-deficient mice develop and live normally, expression of amino proximally truncated PrP(C) (DeltaPrP) or of its structural homolog Doppel (Dpl) causes cerebellar degeneration that is prevented by coexpression of full-length PrP(C). We now report that mice expressing DeltaPrP or Dpl suffer from widespread leukoencephalopathy. Oligodendrocyte-specific expression of full-length PrP(C) under control of the myelin basic protein (MBP) promoter repressed leukoencephalopathy and vastly extended survival but did not prevent cerebellar granule cell (CGC) degeneration. Conversely, neuron-specific PrP(C) expression under control of the neuron-specific enolase (NSE) promoter antagonized CGC degeneration but not leukoencephalopathy. PrP(C) was found in purified myelin and in cultured oligodendrocytes of both wild-type and MBP-PrP transgenic mice but not in NSE-PrP mice. These results identify white-matter damage as an extraneuronal PrP-associated pathology and suggest a previously unrecognized role of PrP(C) in myelin maintenance.
authors.affiliation: Institute of Neuropathology, University Hospital of Zurich, CH-8091 Zurich, Switzerland.
authors.forename: Ivan
authors.initials: I
authors.lastname: Radovanovic
authors.forename: Nathalie
authors.initials: N
authors.lastname: Braun
authors.forename: Olivier T
authors.initials: OT
authors.lastname: Giger
authors.forename: Kirsten
authors.initials: K
authors.lastname: Mertz
authors.forename: Gino
authors.initials: G
authors.lastname: Miele
authors.forename: Marco
authors.initials: M
authors.lastname: Prinz
authors.forename: Beatriz
authors.initials: B
authors.lastname: Navarro
authors.forename: Adriano
authors.initials: A
authors.lastname: Aguzzi
mesh_terms: D000367:Age Factors; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D002493:Central Nervous System Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D058851:GPI-Linked Proteins; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D020287:In Situ Nick-End Labeling / Q000379:methods; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009154:Mutation; D004676:Myelin Basic Protein / Q000235:genetics / Q000378:metabolism*; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D009836:Oligodendroglia / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D010751:Phosphopyruvate Hydratase / Q000235:genetics; D018621:PrPC Proteins / Q000172:deficiency*; D011328:Prions / Q000737:chemistry / Q000235:genetics / Q000472:pathogenicity*; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational
chemical_list: D058851:GPI-Linked Proteins; D005904:Glial Fibrillary Acidic Protein; D004676:Myelin Basic Protein; D018621:PrPC Proteins; D011328:Prions; C122036:Prnd protein, mouse; D010751:Phosphopyruvate Hydratase