Truncated prion protein and Doppel are myelinotoxic in the absence of oligodendrocytic PrPC.
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.
Radovanovic
Ivan
I
Institute of Neuropathology, University Hospital of Zurich, CH-8091 Zurich, Switzerland.
Braun
Nathalie
N
Giger
Olivier T
OT
Mertz
Kirsten
K
Miele
Gino
G
Prinz
Marco
M
Navarro
Beatriz
B
Aguzzi
Adriano
A
D000367:Age Factors; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D002493:Central Nervous System Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D058851:GPI-Linked Proteins; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D020287:In Situ Nick-End Labeling / Q000379:methods; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009154:Mutation; D004676:Myelin Basic Protein / Q000235:genetics / Q000378:metabolism*; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D009836:Oligodendroglia / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D010751:Phosphopyruvate Hydratase / Q000235:genetics; D018621:PrPC Proteins / Q000172:deficiency*; D011328:Prions / Q000737:chemistry / Q000235:genetics / Q000472:pathogenicity*; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational
D058851:GPI-Linked Proteins; D005904:Glial Fibrillary Acidic Protein; D004676:Myelin Basic Protein; D018621:PrPC Proteins; D011328:Prions; C122036:Prnd protein, mouse; D010751:Phosphopyruvate Hydratase