Failure of Prion Protein Oxidative Folding Guides the Formation of Toxic Transmembrane Forms

• Published in: The Journal of biological chemistry Vol. 287; no. 44; pp. 36693 - 36701
• Main Authors: Lisa, Silvia, Domingo, Beatriz, Martínez, Javier, Gilch, Sabine, Llopis, Juan F., Schätzl, Hermann M., Gasset, María
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.10.2012; American Society for Biochemistry and Molecular Biology
• Subjects: Aging; Amino Acid Substitution; Animals; Cell Death; Cell Line; Cell Survival; Cystine - metabolism; Disulfide; Endoplasmic Reticulum Stress; Membrane Proteins; Mice; Molecular Bases of Disease; Mutant Proteins - genetics; Mutant Proteins - metabolism; Neurodegeneration; Oxidation-Reduction; Prion Protein; Prions; Prions - genetics; Prions - metabolism; Protein Folding; Protein Misfolding; Protein Processing, Post-Translational; Protein Structure, Tertiary; Protein Transport; Toxic Proteins; Transmembrane Forms; Membrane Proteins; Protein Misfolding; Prion Protein; Toxic Proteins; Neurodegeneration; Prions; Transmembrane Forms; Cell Death; Disulfide; Aging
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.398776

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. Background:In vivo folding could play an essential role in prion neurodegenerations. Results: Artificial mutants causing labile PrP folds when expressed in cells originate toxic CtmPrP featured by the absence of the intramolecular disulfide bond. Conclusion: Oxidative folding impairment facilitates the formation of the toxic PrP forms. Significance: Unveiling the mechanism facilitating the formation of toxic PrP forms is crucial for the understanding and prevention of prion disorders.