Pharmacological chaperone for the structured domain of human prion protein

Nicoll, Andrew J.; Trevitt, Clare R.; Tattum, M. Howard; Risse, Emmanuel; Quarterman, Emma; Ibarra, Amaurys Ávila; Wright, Connor; Jackson, Graham S.; Sessions, Richard B.; Farrow, Mark A.; Waltho, Jonathan P.; Clarke, Anthony R.; Collinge, John

doi:10.1073/pnas.1009062107

Cited by 73 publications

(80 citation statements)

References 59 publications

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“…Despite extensive investigations, the physiological function of PrP C in healthy organisms as well as the mechanistic aspects of its pathophysiological role remain elusive (4)(5)(6)(7)(8)(9). Although the PrP Sc form found in diseased tissue has been intensively studied, other approaches underline the importance of PrP C as a potential target for TSE prevention and medical intervention after outbreak of the disease (10)(11)(12), with a special focus on rigid-loop cellular prion proteins (RL-PrP C s) (11,(13)(14)(15), which are investigated in this paper.…”

Section: T Ransmissible Spongiform Encephalopathies (Tses) Includementioning

confidence: 99%

Structural plasticity of the cellular prion protein and implications in health and disease

Christen¹,

Damberger²,

Pérez³

et al. 2013

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

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Two lines of transgenic mice expressing mouse/elk and mouse/ horse prion protein (PrP) hybrids, which both form a well-structured β2-α2 loop in the NMR structures at 20°C termed rigid-loop cellular prion proteins (RL-PrP C ), presented with accumulation of the aggregated scrapie form of PrP in brain tissue, and the mouse/ elk hybrid has also been shown to develop a spontaneous transmissible spongiform encephalopathy. Independently, there is in vitro evidence for correlations between the amino acid sequence in the β2-α2 loop and the propensity for conformational transitions to disease-related forms of PrP. To further contribute to the structural basis for these observations, this paper presents a detailed characterization of RL-PrP C conformations in solution. A dynamic local conformational polymorphism involving the β2-α2 loop was found to be evolutionarily preserved among all mammalian species, including those species for which the WT PrP forms an RL-PrP C . The interconversion between two ensembles of PrP C conformers that contain, respectively, a 3 10 -helix turn or a type I β-turn structure of the β2-α2 loop, exposes two different surface epitopes, which are analyzed for their possible roles in the still evasive function of PrP C in healthy organisms and/or at the onset of a transmissible spongiform encephalopathy. Creutzfeldt-Jakob disease in humans, scrapie in sheep and goats, bovine spongiform encephalopathy in cattle, and chronic wasting disease (CWD) in elk and deer (1-3). A common feature of these diseases is the conversion of the cellular form of the prion protein (PrP C ) found in healthy organisms into aggregated isoforms (PrP Sc ), which are deposited primarily in the brain of the diseased individuals (1, 4). Despite extensive investigations, the physiological function of PrP C in healthy organisms as well as the mechanistic aspects of its pathophysiological role remain elusive (4-9). Although the PrP Sc form found in diseased tissue has been intensively studied, other approaches underline the importance of PrP C as a potential target for TSE prevention and medical intervention after outbreak of the disease (10-12), with a special focus on rigid-loop cellular prion proteins (RL-PrP C s) (11,(13)(14)(15), which are investigated in this paper.A common PrP C fold for a globular domain formed by the polypeptide segment of residues 125-228 in mouse PrP (mPrP) [see Schätzl et al. (16) for the numeration in different species], with three α-helices and a short two-stranded antiparallel β-sheet, has been observed for the cellular prion proteins of all mammalian species studied so far (17-27). For WT PrP of most species, parts of the backbone amide group NMR signals of residues in a loop between a β-strand, β2, and a helix, α2, are not observable in NMR spectra recorded with aqueous solutions at pH 4.5 and 20°C at a 1 H resonance frequency of 500 MHz (or higher) because of line broadening by conformational exchange; therefore, the β2-α2 loop in these PrP C s is poorly defined in NMR structures determined un...

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Section: T Ransmissible Spongiform Encephalopathies (Tses) Includementioning

confidence: 99%

Structural plasticity of the cellular prion protein and implications in health and disease

Christen¹,

Damberger²,

Pérez³

et al. 2013

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

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“…The effects of individual extracts on the NMR spectra of recombinant human prion protein (huPrP 91-231 ) were probed using a 15 N-HSQC-perturbation assay (Nicoll et al, 2010). Only the n-butanol extract caused any perturbation of the protein resonances, which manifested as an attenuation of specific resonances in the spectrum (Fig.…”

Section: Interaction With Human Prion Proteinmentioning

confidence: 99%

Non-toxic Salvia sclareoides Brot. extracts as a source of functional food ingredients: Phenolic profile, antioxidant activity and prion binding properties

et al. 2012

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a b s t r a c tSalvia sclareoides is an aromatic herb native to Portugal, of which phenolic content (Folin-Ciocalteau method), chemical profile (HPLC/DAD), antioxidant activity (DPPH, b-carotene/linoleic acid assays), acute toxicity (MTT method, adapted for non-adherent cells), genotoxicity (short-term chromosomal aberration assay) and prion binding properties were evaluated in the acetone, water, ethanol, methanol and n-butanol extracts. The latter presented the highest phenolic content and antioxidant activity (DPPH assay), and was the single one with the flavonoids (+)-catechin, kaempferol O-glucoside and quercetin. Vanillic acid was the major component of all extracts but gallic, gentisic, caffeic, syringic, coumaric and ferulic acids were also found in some extracts. Only the n-butanol extract had components binding to the cellular form of human prion protein detected by NMR which showed specificity for two regions of the folded domain and for the unstructured N-terminal region. Extracts were not cytotoxic nor genotoxic, reinforcing the potential of S. sclareoides for nutraceutical purposes.

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“…Compounds targeting prevention of PrP misfolding have been aggressively pursued as therapeutics. Cells chronically infected with rodent prions are used as a means either to screen compounds inhibiting PrP Sc accumulation (1)(2)(3)(4)(5) or to confirm the proposed antiprion effects of compounds discovered by other means (6,7). Such strategies rest on the assumption that compounds with efficacy against experimentally adapted rodent prions will be effective against naturally occurring prions, in particular those causing human diseases.…”

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confidence: 99%

Quinacrine promotes replication and conformational mutation of chronic wasting disease prions

Bian

Kang

Telling

2014

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

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Quinacrine's ability to reduce levels of pathogenic prion protein (PrP Sc ) in mouse cells infected with experimentally adapted prions led to several unsuccessful clinical studies in patients with prion diseases, a 10-y investment to understand its mechanism of action, and the production of related compounds with expectations of greater efficacy. We show here, in stark contrast to this reported inhibitory effect, that quinacrine enhances deer and elk PrP Sc accumulation and promotes propagation of prions causing chronic wasting disease (CWD), a fatal, transmissible, neurodegenerative disorder of cervids of uncertain zoonotic potential. Surprisingly, despite increased prion titers in quinacrine-treated cells, transmission of the resulting prions produced prolonged incubation times and altered PrP Sc deposition patterns in the brains of diseased transgenic mice. This unexpected outcome is consistent with quinacrine affecting the intrinsic properties of the CWD prion. Accordingly, quinacrine-treated CWD prions were comprised of an altered PrP Sc conformation. Our findings provide convincing evidence for drug-induced conformational mutation of prions without the prerequisite of generating drug-resistant variants of the original strain. More specifically, they show that a drug capable of restraining prions in one species/strain setting, and consequently used to treat human prion diseases, improves replicative ability in another and therefore force reconsideration of current strategies to screen antiprion compounds.prion therapeutics | prion enhancing drugs P rions are protein-based infectious agents that cause an increasing variety of fatal, infectious neurodegenerative disorders, frequently as epidemics. Variant Creutzfeldt-Jakob disease (CJD) resulting from bovine spongiform encephalopathy exemplifies prion zoonosis, and the continued, unpredictable emergence of additional epidemics in other species, particularly chronic wasting disease (CWD) in deer, elk, and moose, raises additional concerns. Its unprecedented contagious spread, widening host range, and conflicting evidence surrounding its zoonotic potential place CWD at the forefront of public health concerns. Although the notion, that prion replication occurs by corruption of host-encoded cellular prion protein (PrP C ) by abnormally conformed PrP Sc , is now widely accepted, the details of this mechanism remain enigmatic.Except under certain experimental conditions, treatments capable of arresting or of effectively modifying the course of disease do not exist for prion disorders. Compounds targeting prevention of PrP misfolding have been aggressively pursued as therapeutics. Cells chronically infected with rodent prions are used as a means either to screen compounds inhibiting PrP Sc accumulation (1-5) or to confirm the proposed antiprion effects of compounds discovered by other means (6, 7). Such strategies rest on the assumption that compounds with efficacy against experimentally adapted rodent prions will be effective against naturally occurring prions, in ...

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Pharmacological chaperone for the structured domain of human prion protein

Cited by 73 publications

References 59 publications

Structural plasticity of the cellular prion protein and implications in health and disease

Structural plasticity of the cellular prion protein and implications in health and disease

Non-toxic Salvia sclareoides Brot. extracts as a source of functional food ingredients: Phenolic profile, antioxidant activity and prion binding properties

Quinacrine promotes replication and conformational mutation of chronic wasting disease prions

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