Truncated prion protein and Doppel are myelinotoxic in the absence of oligodendrocytic PrPC

J Neurosci. 2005 May 11;25(19):4879-88. 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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Blotting, Western / methods
  • Central Nervous System Diseases / genetics
  • Central Nervous System Diseases / metabolism
  • Central Nervous System Diseases / pathology
  • GPI-Linked Proteins
  • Glial Fibrillary Acidic Protein / metabolism
  • 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
  • Neurons / metabolism
  • Neurons / pathology
  • Neurons / ultrastructure
  • Oligodendroglia / metabolism*
  • Oligodendroglia / pathology*
  • Oligodendroglia / ultrastructure
  • Phosphopyruvate Hydratase / genetics
  • PrPC Proteins / deficiency*
  • Prions / chemistry
  • Prions / genetics
  • Prions / pathogenicity*
  • Protein Conformation
  • Protein Processing, Post-Translational


  • GPI-Linked Proteins
  • Glial Fibrillary Acidic Protein
  • Myelin Basic Protein
  • PrPC Proteins
  • Prions
  • Prnd protein, mouse
  • Phosphopyruvate Hydratase