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The Journal of Neuroscience, January 15, 2003, 23(2):462-469
In Vivo and In Vitro Neurotoxicity
of the Human Prion Protein (PrP) Fragment P118-135
Independently of PrP Expression
Joëlle
Chabry1,
Christiane
Ratsimanohatra2, *,
Isabelle
Sponne3, *,
Pierre-Paul
Elena2,
Jean-Pierre
Vincent1, and
Thierry
Pillot3
1 Institut de Pharmacologie Moléculaire et
Cellulaire, Unité Mixte de Recherche 6097, Centre National de la
Recherche Scientifique, 06560 Valbonne, France, 2 Iris
Pharma, Les Nertières, 06610 La Gaude, France, and
3 Institut National de la Santé et de la Recherche
Médicale, Université de Nancy I, 54505 Vand uvre-les-Nancy, France
We recently demonstrated that the 118-135 putative transmembrane
domain of prion protein (PrP) exhibited membrane fusogenic properties and induced apoptotic neuronal cell death of rat cortical neurons, independently of its aggregation state. The aim of the present
study was to analyze the in vivo neurotoxicity of the prion fragment P118-135 and to evaluate the potential role of the
physiological isoform of PrP in the P118-135-induced cell death. Here,
we demonstrate that the nonfibrillar P118-135 is cytotoxic to retinal
neurons in vivo as monitored by intravitreal inoculation
and recording of the electrical activity of retina and tissue
examination. Moreover, knock-out PrP gene mice exhibit similar
sensitivity to the nonfibrillar P118-135-induced cell death and
electrical perturbations, strongly suggesting that cell death occurs
independently of PrP expression. Interestingly, a variant nonfusogenic
P118-135 peptide (termed P118-135 ) had no effects on in
vivo neuronal viability, suggesting that the P118-135-induced cell death is mediated by its membrane destabilizing properties. These
data have further been confirmed in vitro. We show that the fusogenic peptide P118-135 induces death of cultured neurons from
both wild-type and knock-out PrP gene mice via an apoptotic-mediated pathway, involving early caspase activation and DNA fragmentation. Altogether these results emphasize the neurotoxicity of the fusogenic nonfibrillar PrP transmembrane domain and indicate that fibril formation and PrP expression are not obligatory requirements for neuronal cell death. The use of synthetic prion peptides could provide
insights into the understanding of neuronal loss mechanisms that take
place during the development of the various types of spongiform encephalopathies.
Key words:
prion peptide; retina; apoptosis; in
vivo; caspase activities; electroretinogram
*
C.R. and I.S. contributed equally to this work.
Copyright © 2003 Society for Neuroscience 0270-6474/03/232462-08$05.00/0
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