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

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Abstract
The cellular prion protein PrPCconfers 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(ΔPrP) 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 ΔPrP or Dpl suffer from widespread leukoencephalopathy. Oligodendrocyte-specific expression of full-length PrPCunder 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 PrPCexpression under control of the neuron-specific enolase (NSE) promoter antagonized CGC degeneration but not leukoencephalopathy. PrPCwas 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 PrPCin myelin maintenance.