Neurobiology of Disease Truncated Prion Protein and Doppel Are Myelinotoxic in the Absence of Oligodendrocytic PrP

The cellular prion protein PrP C confers susceptibility to transmissible spongiform encephalopathies, yet its normal function is unknown. Although PrP -deficient mice develop and live normally, expression of amino proximally truncated PrP C ( PrP) or of its structural homolog Doppel (Dpl) causes cerebellar degeneration that is prevented by coexpression of full-length PrP . We now report that mice expressing PrP 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.