Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 287, Issue 44, Pages 36693-36701Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.398776
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Funding
- Spanish Ministerio de Economia y Competitividad Grant [BFU2009-07971]
- Fundacion Cien-Fundacion Reina Sofia grant
- Alberta Prions Research Institute grant
- Formacion del Personal Investigador Ph.D. grants
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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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