Failure of Prion Protein Oxidative Folding Guides the Formation of Toxic Transmembrane Forms |
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| Authors: | Silvia Lisa Beatriz Domingo Javier Martínez Sabine Gilch Juan F. Llopis Hermann M. Sch?tzl María Gasset |
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| Affiliation: | From the ‡Instituto Química-Física “Rocasolano,” Consejo Superior de Investigaciones Científicas, Serrano 119, 28006 Madrid, Spain.;the §Centro Regional de Investigaciones Biomédicas and Facultad de Medicina, Universidad de Castilla-La Mancha, 02006 Albacete, Spain, and ;the ¶Departments of Veterinary Sciences and Molecular Biology, University of Wyoming, Laramie, Wyoming 82071 |
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| Abstract: | The mechanism by which pathogenic mutations in the globular domain of the cellular prion protein (PrPC) increase the likelihood of misfolding and predispose to diseases is not yet known. Differences in the evidences provided by structural and metabolic studies of these mutants suggest that in vivo folding could be playing an essential role in their pathogenesis. To address this role, here we use the single or combined M206S and M213S artificial mutants causing labile folds and express them in cells. We find that these mutants are highly toxic, fold as transmembrane PrP, and lack the intramolecular disulfide bond. When the mutations are placed in a chain with impeded transmembrane PrP formation, toxicity is rescued. These results suggest that oxidative folding impairment, as on aging, can be fundamental for the genesis of intracellular neurotoxic intermediates key in prion neurodegenerations. |
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| Keywords: | Cell Death Disulfide Membrane Proteins Neurodegeneration Prions Protein Misfolding Aging Prion Protein Toxic Proteins Transmembrane Forms |
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