Prion Proteins with Different Conformations Accumulate in Gerstmann-Sträussler-Scheinker Disease Caused by A117V and F198S Mutations

Piccardo, Pedro; Liepnieks, Juris J.; William, Albert; Dlouhy, Stephen R.; Farlow, Martin R.; Young, Katherine; Nochlin, David; Bird, Thomas D.; Nixon, Randal R.; Ball, Melvyn J.; DeCarli, Charles; Bugiani, Orso; Tagliavini, Fabrizio; Benson, Merrill D.; Ghetti, Bernardino

doi:10.1016/s0002-9440(10)64692-5

Cited by 80 publications

(66 citation statements)

References 35 publications

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“…However, peptides mimicking fragments of PrP-res associated with familial forms of TSE disease seem to have different mechanisms of neurotoxicity, and the same may be true for other PrP fragments found in sporadic CJD. Peptides derived from the amyloidogenic core of the 7-8-kDa PrP-res fragment present in patients with Gerstmann-Straü ssler-Scheinker syndrome (12)(13)(14)(15), are only toxic to neurons that express PrP (48,49). In contrast, a larger C-terminal, protease-resistant fragment associated with familial CJD (E200K mutation) (10) and similar to those described for sporadic Creutzfeldt-Jakob disease (45)(46)(47)) is toxic to neurons that do not express PrP (50).…”

Section: Discussionmentioning

confidence: 99%

Flexible N-terminal Region of Prion Protein Influences Conformation of Protease-resistant Prion Protein Isoforms Associated with Cross-species Scrapie Infection in Vivo and in Vitro

Lawson¹,

Priola

Meade-White

et al. 2004

Journal of Biological Chemistry

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Transmissible spongiform encephalopathy (TSE) diseases are characterized by the accumulation in brain of an abnormal protease-resistant form of the host-encoded prion protein (PrP), PrP-res. PrP-res conformation differs among TSE agents derived from various sources, and these conformational differences are thought to influence the biological characteristics of these agents. In this study, we introduced deletions into the flexible N-terminal region of PrP (residues 34 -124) and investigated the effect of this region on the conformation of PrP-res generated in an in vitro cell-free conversion assay. PrP deleted from residues 34 to 99 generated 12-16-kDa protease-resistant bands with intact C termini but variable N termini. The variable N termini were the result of exposure of new protease cleavage sites in PrP-res between residues 130 and 157, suggesting that these new cleavage sites were caused by alterations in the conformation of the PrP-res generated. Similarly truncated 12-16-kDa PrP bands were also identified in brain homogenates from mice infected with mouse-passaged hamster scrapie as well as in the cellfree conversion assay using conditions that mimicked the hamster/mouse species barrier to infection. Thus, by its effects on PrP-res conformation, the flexible N-terminal region of PrP seemed to influence TSE pathogenesis and cross-species TSE transmission.

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Section: Discussionmentioning

confidence: 99%

Flexible N-terminal Region of Prion Protein Influences Conformation of Protease-resistant Prion Protein Isoforms Associated with Cross-species Scrapie Infection in Vivo and in Vitro

Lawson¹,

Priola

Meade-White

et al. 2004

Journal of Biological Chemistry

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“…Cell studies indicate that the instability of the globular fold interferes with GPI-anchor attachment and subsequent cellular processing [155,156]. In vivo, these mutations typically cause a prolonged duration of disease [157] and can lead to abnormal PrP Sc formation [158]. Although correlations between simulation of recPrP and disease are specu-lative, they indicate how MD simulation helps to uncover detailed molecular effects that may be important for the development of familial prion disease.…”

Section: Mutations In the Hydrophobic Corementioning

confidence: 99%

Molecular Dynamics as an Approach to Study Prion Protein Misfolding and the Effect of Pathogenic Mutations

Kamp

Daggett

2011

Topics in Current Chemistry

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“…One of the key arguments in favor of the protein-only model is the link between familial prion diseases and specific mutations in the gene coding for human prion protein (I, [7][8]. While the pathological hallmark of prion diseases has been sufficiently characterized, the structural link between pathological mutations and disease remains more uncertain (9)(10).…”

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confidence: 99%

Identification of a Conserved N-Capping Box Important for the Structural Autonomy of the Prion α3-Helix: The Disease Associated D202N Mutation Destabilizes the Helical Conformation

Gallo

Paludi

Cicero

et al. 2005

Int J Immunopathol Pharmacol

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Peptides corresponding to three alpha helices present in the C-terminal region of the human prion protein have been synthesized and their structural autonomy analyzed by circular dichroism (CD) and NMR spectroscopy. The results obtained indicate that the protein fragment corresponding to the a3-helix, in contrast to al and a2 peptides, shows a complete structural autonomy. The chemical shifts values found for NH and CHa resonances of the isolated a3 peptide, formed by 30 aminoacid residues, were markedly and surprisingly similar to the corresponding values of the a3-helix in the protein. The structural autonomy of the a3-helix is profoundly determined by the presence of the conserved capping box and, in part, by the ionic bond formed between Glu200 and Lys204. On the basis of these observations a novel PrP consensus pattern, centered on the a3-helix region, has been defined. The data indicate that this autonomous and highly conserved region of the Pr'P'Tikely plays a critical role in folding and stability. This gives an explanation of why many of pathogenic mutations occur in this part of the molecule, sharing relevant effects on the overall protein conformation. In particular the D202N capping mutation almost completely destabilizes the isolated a3 peptide. While it is well known that the D202N substitution is associated with a GSS disease, the possible structural basis of this fatal pathology has never been investigated. We propose that a lower a3-helical propensity leading to a major destabilization of the Pr'P" molecule initiates the pathogenic process associated with D202N capping mutation.

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Prion Proteins with Different Conformations Accumulate in Gerstmann-Sträussler-Scheinker Disease Caused by A117V and F198S Mutations

Cited by 80 publications

References 35 publications

Flexible N-terminal Region of Prion Protein Influences Conformation of Protease-resistant Prion Protein Isoforms Associated with Cross-species Scrapie Infection in Vivo and in Vitro

Flexible N-terminal Region of Prion Protein Influences Conformation of Protease-resistant Prion Protein Isoforms Associated with Cross-species Scrapie Infection in Vivo and in Vitro

Molecular Dynamics as an Approach to Study Prion Protein Misfolding and the Effect of Pathogenic Mutations

Identification of a Conserved N-Capping Box Important for the Structural Autonomy of the Prion α3-Helix: The Disease Associated D202N Mutation Destabilizes the Helical Conformation

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