NR AUDQ
AU Radovanovic,I.; Braun,N.; Giger,O.T.; Mertz,K.; Miele,G.; Prinz,M.; Navarro,B.; Aguzzi,A.
TI Truncated prion protein and Doppel are myelinotoxic in the absence of oligodendrocytic PrPc
QU Journal of Neuroscience 2005 May 11; 25(19): 4879-88
IA http://www.jneurosci.org/cgi/content/full/25/19/4879
PT journal article
AB The cellular prion protein PrPc confers susceptibility to transmissible spongiform encephalopathies, yet its normal function is unknown. Although PrPc-deficient mice develop and live normally, expression of amino proximally truncated PrPc (DeltaPrP) or of its structural homolog Doppel (Dpl) causes cerebellar degeneration that is prevented by coexpression of full-length PrPc. We now report that mice expressing DeltaPrP or Dpl suffer from widespread leukoencephalopathy. Oligodendrocyte-specific expression of full-length PrPc 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 PrPc expression under control of the neuron-specific enolase (NSE) promoter antagonized CGC degeneration but not leukoencephalopathy. PrPc 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 PrPc in myelin maintenance.
MH Age Factors; Animals; Blotting, Western/methods; Central Nervous System Diseases/genetics/metabolism/pathology; Comparative Study; Glial Fibrillary Acidic Protein/metabolism; In Situ Nick-End Labeling/methods; Mice; Mice, Transgenic; Microscopy, Electron, Transmission/methods; Mutation; Myelin Basic Proteins/genetics/*metabolism; Nerve Degeneration/genetics/metabolism/pathology; Neurons/metabolism/pathology/ultrastructure; Oligodendroglia/*metabolism/*pathology/ultrastructure; Phosphopyruvate Hydratase/genetics; PrPc Proteins/*deficiency; Prions/chemistry/genetics/*pathogenicity; Protein Conformation; Protein Processing, Post-Translational; Research Support, Non-U.S. Gov't
AD Institute of Neuropathology, University Hospital of Zürich, CH-8091 Zürich, Switzerland.
SP englisch
PO USA