Truncated Prion Protein and Doppel Are Myelinotoxic in the Absence of Oligodendrocytic PrPC

• Published in: The Journal of neuroscience 2005-05, Vol.25 (19), p.4879-4888
• Main Authors: Radovanovic, Ivan, Braun, Nathalie, Giger, Olivier T, Mertz, Kirsten, Miele, Gino, Prinz, Marco, Navarro, Beatriz, Aguzzi, Adriano
• Format: Article
• Language: English
• Subjects: Age Factors; Animals; Blotting, Western - methods; Central Nervous System Diseases - genetics; Central Nervous System Diseases - metabolism; Central Nervous System Diseases - pathology; Glial Fibrillary Acidic Protein - metabolism; GPI-Linked Proteins; In Situ Nick-End Labeling - methods; Mice; Mice, Transgenic; Microscopy, Electron, Transmission - methods; Mutation; Myelin Basic Protein - genetics; Myelin Basic Protein - metabolism; Nerve Degeneration - genetics; Nerve Degeneration - metabolism; Nerve Degeneration - pathology; Neurobiology of Disease; Neurons - metabolism; Neurons - pathology; Neurons - ultrastructure; Oligodendroglia - metabolism; Oligodendroglia - pathology; Oligodendroglia - ultrastructure; Phosphopyruvate Hydratase - genetics; Prions - chemistry; Prions - genetics; Prions - pathogenicity; Protein Conformation; Protein Processing, Post-Translational; PrPC Proteins - deficiency
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.0328-05.2005

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.