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J. Biol. Chem., Vol. 280, Issue 24, 23114-23121, June 17, 2005

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Amidation and Structure Relaxation Abolish the Neurotoxicity of the Prion Peptide PrP106–126 in Vivo and in Vitro^*

Ann-Louise Bergström, Henriette Cordes, Nicole Zsurger¶, Peter M. H. Heegaard, Henning Laursen||, and Joëlle Chabry¶

From the Danish Institute for Food and Veterinary Research, Department of Veterinary Diagnostics and Research, Bülowsvej 27, 1790 Copenhagen V, Denmark, ^¶Institute de Pharmacologie Moléculaire et Cellulaire, CNRS, Unité Mixte de Recherche 6097, 660 Route des Lucioles, Sophia Antipolis, 06560 Valbonne, France, and the ^||Laboratory of Neuropathology, Rigshospitalet, 2100 Copenhagen Ø, Denmark

One of the major pathological hallmarks of transmissible spongiform encephalopathies (TSEs) is the accumulation of a pathogenic (scrapie) isoform (PrP^Sc) of the cellular prion protein (PrP^C) primarily in the central nervous system. The synthetic prion peptide PrP106–126 shares many characteristics with PrP^Sc in that it shows PrP^C-dependent neurotoxicity both in vivo and in vitro. Moreover, PrP106–126 in vitro neurotoxicity has been closely associated with the ability to form fibrils. Here, we studied the in vivo neurotoxicity of molecular variants of PrP106–126 toward retinal neurons using electroretinographic recordings in mice after intraocular injections of the peptides. We found that amidation and structure relaxation of PrP106–126 significantly reduced the neurotoxicity in vivo. This was also found in vitro in primary neuronal cultures from mouse and rat brain. Thioflavin T binding studies showed that amidation and structure relaxation significantly reduced the ability of PrP106–126 to attain fibrillar structures in physiological salt solutions. This study hence supports the assumption that the neurotoxic potential of PrP106–126 is closely related to its ability to attain secondary structure.

Received for publication, January 6, 2005 , and in revised form, April 7, 2005.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. E-mail: alb{at}dfvf.dk.

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