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A Nonfibrillar Form of the Fusogenic Prion Protein Fragment [118‐135] Induces Apoptotic Cell Death in Rat Cortical Neurons
Author(s) -
Pillot Thierry,
Drouet Béatrice,
PinçonRaymond Martine,
Vandekerckhove Joël,
Rosseneu Maryvonne,
Chambaz Jean
Publication year - 2000
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2000.0752298.x
Subject(s) - neurotoxicity , peptide , programmed cell death , microbiology and biotechnology , biology , scrapie , apoptosis , neuroprotection , biochemistry , amino acid , chemistry , biophysics , toxicity , neuroscience , prion protein , medicine , disease , organic chemistry
Neuronal loss is a salient feature of prion diseases.However, its cause and mechanism, particularly its relationship with theaccumulation and precipitation of the pathogenic, protease‐resistant isoformPrP Sc of the cellular prion protein PrP C , are still anenigma. Several studies suggest that neuronal loss could occur through aprocess of programmed cell death, which is consistent with the lack ofinflammation in these conditions. By analogy with the pathological eventsoccurring during the development of Alzheimer's disease, controversies stillexist regarding the relationship between amyloidogenesis, prion aggregation,and neuronal loss. We recently demonstrated that a prion protein fragment(118‐135) displayed membrane‐destabilizing properties and was able to induce,in a nonfibrillar form, the fusion of unilamellar liposomes. To unravel themechanism of prion protein neurotoxicity, we characterize the effects of thehuman Pr[118‐135] peptide on rat cortical neurons. We demonstrate that lowconcentrations of the Pr[118‐135] peptide, in a nonfibrillar form, induce atime‐ and dose‐ dependent apoptotic cell death, including caspase activation,DNA condensation, and fragmentation. This toxicity might involve oxidativestress, because antioxidant molecules, such as probucol and propyl gallate,protect neurons against prion peptide toxicity. By contrast, a nonfusogenicvariant Pr[118‐135, 0°] peptide, which displays the same amino acidcomposition but several amino acid permutations, is not toxic to corticalneurons, which emphasizes the critical role of the fusogenic properties of theprion peptide in its neurotoxicity. Taken together, our results suggest thatthe interaction between the Pr[118‐135] peptide and the plasma membrane ofneurons might represent an early event in a cascade leading toneurodegeneration.