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

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 (?PrP) 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 ?PrP 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.