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The Journal of Neuroscience, May 11, 2005, 25(19):4879-4888; doi:10.1523/JNEUROSCI.0328-05.2005

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

Ivan Radovanovic, ^* Nathalie Braun, ^* Olivier T. Giger, Kirsten Mertz, Gino Miele, Marco Prinz, Beatriz Navarro, and Adriano Aguzzi

Institute of Neuropathology, University Hospital of Zurich, CH-8091 Zurich, Switzerland

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 (PrP) 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 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.

Key words: cerebellum; spinal cord; prion protein; Doppel; leukoencephalopathy; neurodegeneration

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Received Jan 24, 2005; revised April 4, 2005; accepted April 10, 2005.

This article has been cited by other articles:

				A. Aguzzi and A. M. Calella Prions: Protein Aggregation and Infectious Diseases Physiol Rev, October 1, 2009; 89(4): 1105 - 1152. [Abstract] [Full Text] [PDF]

				R. Linden, V. R. Martins, M. A. M. Prado, M. Cammarota, I. Izquierdo, and R. R. Brentani Physiology of the Prion Protein Physiol Rev, April 1, 2008; 88(2): 673 - 728. [Abstract] [Full Text] [PDF]

				O. Nicolas, R. Gavin, N. Braun, J. M. Urena, X. Fontana, E. Soriano, A. Aguzzi, and J. Antonio del Rio Bcl-2 overexpression delays caspase-3 activation and rescues cerebellar degeneration in prion-deficient mice that overexpress amino-terminally truncated prion FASEB J, October 1, 2007; 21(12): 3107 - 3117. [Abstract] [Full Text] [PDF]

				J. Dong, A. Li, N. Yamaguchi, S. Sakaguchi, and D. A. Harris Doppel Induces Degeneration of Cerebellar Purkinje Cells Independently of Bax Am. J. Pathol., August 1, 2007; 171(2): 599 - 607. [Abstract] [Full Text] [PDF]

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