Reversion of prion protein conformational changes by synthetic b-sheet breaker peptides

Soto, Claudio; Saborı́o, Gabriela P.; Aucouturier, Pièrre; Wısnıewskı, Thomas; Prelli, Frances; Kascsak, Richard J.; Méndez, Enrique; Harris, David A.; Ironside, James W.; Tagliavini, Fabrizio; Carp, Richard I.; Frangione, Blas

doi:10.1016/s0140-6736(99)11419-3

Cited by 265 publications

(165 citation statements)

References 26 publications

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“…Several drugs have been shown to diminish or abolish PrP Sc in prion-infected cell cultures, for instance Congo red (29), polyene compounds such as amphothericin (30), pentosan sulfate (31), branched polyamines (32), and ␤-sheet-breaking peptides (33), to mention but a few. In some instances these drugs delayed, but never prevented, the appearance of clinical symptoms and death in experimental animals (34,35).…”

Section: Discussionmentioning

confidence: 99%

“…Several mechanisms may lead to PrP Sc depletion: prevention of PrP C to PrP Sc conversion by stabilization of PrP C , interference with the interaction of PrP C and PrP Sc (36), or sequestration and/or reversion of PrP Sc to a protease-sensitive state (33). In addition, abrogation of PrP C synthesis or prevention of transport to the cell surface could interrupt prion propagation.…”

Section: Discussionmentioning

confidence: 99%

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Scrapie prion protein accumulation by scrapie-infected neuroblastoma cells abrogated by exposure to a prion protein antibody

Enari

Flechsig²,

Weissmann³

2001

Proc. Natl. Acad. Sci. U.S.A.

402

312

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Exposure of susceptible neuroblastoma N2a cells to mouse scrapie prions leads to infection, as evidenced by the continued presence of the scrapie form of the prion protein (PrP Sc ) and infectivity after 300 or more cell doublings. We find that exposure to phosphatidylinositol-specific phospholipase C (PIPLC) or to the monoclonal anti-prion protein (PrP) antibody 6H4 not only prevents infection of susceptible N2a cells but also cures chronically scrapie-infected cultures, as judged by the long-term abrogation of PrP Sc accumulation after cessation of treatment. A nonpassaged, stationary infected culture rapidly loses PrP Sc when exposed to the antibody or PIPLC, indicating that the PrP Sc level is determined by steady state equilibrium between formation and degradation, and that depletion of the cellular form of PrP can interrupt the propagation of PrP Sc . These findings encourage the belief that passive immunization may provide a therapeutic approach to prion disease.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Scrapie prion protein accumulation by scrapie-infected neuroblastoma cells abrogated by exposure to a prion protein antibody

Enari

Flechsig²,

Weissmann³

2001

Proc. Natl. Acad. Sci. U.S.A.

402

312

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“…Other approaches to inducing the folding of proteins have been developed. For example, mini-chaperones that prevent ␤-sheet formation prevent toxic aggregation of amyloid-␤ found in Alzheimer's disease and the PrP protein associated with prion disease (50).…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Chaperone-mediated in Vivo Folding and Stabilization of the P23H-opsin Mutant Associated with Autosomal Dominant Retinitis Pigmentosa

Noorwez¹,

Kuksa²,

Imanishi³

et al. 2003

Journal of Biological Chemistry

187

159

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Protein conformational disorders, which include certain types of retinitis pigmentosa, are a set of inherited human diseases in which mutant proteins are misfolded and often aggregated. Many opsin mutants associated with retinitis pigmentosa, the most common being P23H, are misfolded and retained within the cell. Here, we describe a pharmacological chaperone, 11-cis-7-ring retinal, that quantitatively induces the in vivo folding of P23H-opsin. The rescued protein forms pigment, acquires mature glycosylation, and is transported to the cell surface. Additionally, we determined the temperature stability of the rescued protein as well as the reactivity of the retinal-opsin Schiff base to hydroxylamine. Our study unveils novel properties of P23H-opsin and its interaction with the chromophore. These properties suggest that 11-cis-7-ring retinal may be a useful therapeutic agent for the rescue of P23H-opsin and the prevention of retinal degeneration.

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“…These molecules include polyanions (10)(11)(12)(13)(14), polyene antibiotics (15)(16)(17), Congo red (18,19), iododoxorubicin (20), tetrapyrroles (21,22), branched polyamines (23,24), and modified PrP peptides (25). Unfortunately, the suitability of these compounds for therapy is limited, primarily because of inability to cross the blood-brain barrier and͞or severe toxicity.…”

mentioning

confidence: 99%

Tetracyclines affect prion infectivity

Forloni¹,

Iussich²,

Awan³

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

179

102

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Prion diseases are transmissible neurodegenerative disorders of humans and animals for which no effective treatment is available. Conformationally altered, protease-resistant forms of the prion protein (PrP) termed PrP Sc are critical for disease transmissibility and pathogenesis, thus representing a primary target for therapeutic strategies. Based on previous findings that tetracyclines revert abnormal physicochemical properties and abolish neurotoxicity of PrP peptides in vitro, we tested the ability of these compounds to interact with PrP Sc from patients with the new variant of Creutzfeldt-Jakob disease (vCJD) and cattle with bovine spongiform encephalopathy (BSE). The incubation with tetracycline hydrochloride or doxycycline hyclate at concentrations ranging from 10 M to 1 mM resulted in a dose-dependent decrease in protease resistance of PrP Sc . This finding prompted us to investigate whether tetracyclines affect prion infectivity by using an animal model of disease. Syrian hamsters were injected intracerebrally with 263K scrapie-infected brain homogenate that was coincubated with 1 mM tetracycline hydrochloride, 1 mM doxycycline hyclate, or vehicle solution before inoculation. Hamsters injected with tetracycline-treated inoculum showed a significant delay in the onset of clinical signs of disease and prolonged survival time. These effects were paralleled by a delay in the appearance of magnetic-resonance abnormalities in the thalamus, neuropathological changes, and PrP Sc accumulation. When tetracycline was preincubated with highly diluted scrapie-infected inoculum, one third of hamsters did not develop disease. Our data suggest that these well characterized antibiotics reduce prion infectivity through a direct interaction with PrP Sc and are potentially useful for inactivation of BSE-or vCJD-contaminated products and prevention strategies.

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Reversion of prion protein conformational changes by synthetic b-sheet breaker peptides

Cited by 265 publications

References 26 publications

Scrapie prion protein accumulation by scrapie-infected neuroblastoma cells abrogated by exposure to a prion protein antibody

Scrapie prion protein accumulation by scrapie-infected neuroblastoma cells abrogated by exposure to a prion protein antibody

Pharmacological Chaperone-mediated in Vivo Folding and Stabilization of the P23H-opsin Mutant Associated with Autosomal Dominant Retinitis Pigmentosa

Tetracyclines affect prion infectivity

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