Mutation of the Prion Protein in Libyan Jews with Creutzfeldt–Jakob Disease

Hsiao, Karen; Meiner, Zeev; Kahana, Esther; Cass, Carin; Kahana, Irit; Avrahami, Dana; Scarlato, G.; Abramsky, Oded; Prusiner, Stanley B.; Gabizon, Ruth

doi:10.1056/nejm199104183241604

Cited by 247 publications

(127 citation statements)

References 33 publications

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“…Although amyloid-containing prion plaques are virtually absent in a number of prion diseases Hsiao et al, 1991;McKinley et al, 1991), their presence in others (Gajdusek, 1977;Ghetti et al, 1989Ghetti et al, , 1996Goldfarb et al, 1993;Tagliavini et al, 1994) suggests that the structural feature may be important in the pathology of a subset of the prion diseases. We used two synthetic prion peptides as model systems with which to examine the role of peptide ␤-sheet and amyloid content in the toxicity and membrane binding affinity of the peptides.…”

Section: Discussionmentioning

confidence: 99%

The Role of Prion Peptide Structure and Aggregation in Toxicity and Membrane Binding

Rymer

Good

2000

Journal of Neurochemistry

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Prion diseases are neurodegenerative disorders associated with a conformational change in the normal cellular isoform of the prion protein, PrP C , to an abnormal scrapie isoform, PrP SC . Unlike the ␣-helical PrP C , the protease-resistant core of PrP SC is predominantly ␤-sheet and possesses a tendency to polymerize into amyloid fibrils. We performed experiments with two synthetic human prion peptides, and , to determine how peptide structure affects neurotoxicity and protein-membrane interactions. Peptide solutions possessing ␤-sheet and amyloid structures were neurotoxic to PC12 cells in vitro and bound with measurable affinities to cholesterol-rich phospholipid membranes at ambient conditions, but peptide solutions lacking stable ␤-sheet structures and amyloid content were nontoxic and possessed less than one tenth of the binding affinities of the amyloid-containing peptides. Regardless of structure, the peptide binding affinities to cholesterol-depleted membranes were greatly reduced. These results suggest that the ␤-sheet and amyloid structures of the prion peptides give rise to their toxicity and membrane binding affinities and that membrane binding affinity, especially in cholesterol-rich environments, may be related to toxicity. Our results may have significance in understanding the role of the fibrillogenic cerebral deposits associated with some of the prion diseases in neurodegeneration and may have implications for other amyloidoses. Key Words: Circular dichroismSpongiform encephalopathies-Cell membranes. J. Neurochem. 75, 2536Neurochem. 75, -2545Neurochem. 75, (2000.The prion-related encephalopathies, including scrapie and bovine spongiform encephalopathy in livestock and Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome, and kuru in humans, are neurodegenerative disorders characterized by early synaptic loss, astrocytosis, progressive neuronal loss, and often cerebral protein aggregation and deposition (Gajdusek et al., 1966;Clinton et al., 1993;Fraser, 1993;Jeffrey et al., 1994). These diseases appear to be caused by the posttranslational and conformational transition of the normal cellular prion protein (PrP) isoform, PrP C , into the abnormal and pathogenic PrP isoform, PrP SC (Prusiner, 1982(Prusiner, , 1991Hope and Manson, 1991). Fourier transform infrared spectroscopy and circular dichroism (CD) demonstrate that PrP C is predominantly ␣-helical (42%) with little ␤-sheet structure (3%). However, the protease-resistant core of PrP SC is mostly ␤-sheet (43%) with less ␣-helical structure (30%), and it has a tendency to polymerize into amyloid fibrils (Prusiner et al., 1983;Pan et al., 1993;Safar et al., 1993;Baldwin et al., 1994). Based on these structural measurements, researchers have postulated that PrP SC formation involves a conformational transformation resulting in increased ␤-sheet content (Pan et al., 1993;Safar et al., 1993;Baldwin et al., 1994).Structural changes similar to the PrP C to PrP SC conformational conversion associated with prion diseases ar...

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Section: Discussionmentioning

confidence: 99%

The Role of Prion Peptide Structure and Aggregation in Toxicity and Membrane Binding

Rymer

Good

2000

Journal of Neurochemistry

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“…The present study showed that Mo.E199K PrP, as well as heterologous hamster and hamster/ mouse chimeric PrPs, but not MHM2.del23-88 PrP, could rescue Ngsk Prnp 0/0 mice from Purkinje cell death. Mo.E199K represents the E200K substitution in human PrP, which is commonly found in patients with familial Creutzfeldt-Jakob disease (21). The successful rescue by Mo.E199K strongly indicates that the mutant retains the major aspects of normal PrP function and thus argues against a dominant-negative role for the mutant.…”

Section: D E and F)mentioning

confidence: 99%

“…MH2M PrP has five amino acid substitutions (L108M, V111M, I138M, Y154N, and S169N) from Mo.PrP. The E199K substitution in Mo.E199K PrP corresponds to that found in patients with familial Creutzfeldt-Jakob disease (21). Offspring carrying the transgenes were identified by PCR of tail DNA as described previously (5).…”

mentioning

confidence: 99%

Deletion of N-terminal Residues 23–88 from Prion Protein (PrP) Abrogates the Potential to Rescue PrP-deficient Mice from PrP-like Protein/Doppel-induced Neurodegeneration

Atarashi

Nishida

Shigematsu

et al. 2003

Journal of Biological Chemistry

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“…This finding prompted some investigators to propose that the Libyan Jews had contracted CJD by eating lightly cooked brain from scrapie-infected sheep when they lived in Tripoli prior to emigration. Subsequently, the Libyan Jewish patients were all found to carry a mutation at codon 200 in their prion protein (PrP) gene (14)(15)(16).…”

mentioning

confidence: 99%

Molecular characterization of proteolytic cleavage sites of the Pseudomonas syringae effector AvrRpt2

Chisholm

Dahlbeck

Krishnamurthy

et al. 2005

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

137

138

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Prions are unprecedented infectious pathogens that cause a group of invariably fatal neurodegenerative diseases by an entirely novel mechanism. Prion diseases may present as genetic, infectious, or sporadic disorders, all of which involve modification of the prion protein (PrP). Bovine spongiform encephalopathy (BSE), scrapie of sheep, and Creutzfeldt-Jakob disease (CJD) of humans are among the most notable prion diseases. Prions are transmissible particles that are devoid of nucleic acid and seem to be composed exclusively of a modified protein (PrP Sc ). The normal, cellular PrP (PrP C ) is converted into PrP Sc through a posttranslational process during which it acquires a high ␤-sheet content. The species of a particular prion is encoded by the sequence of the chromosomal PrP gene of the mammals in which it last replicated. In contrast to pathogens carrying a nucleic acid genome, prions appear to encipher strain-specific properties in the tertiary structure of PrP Sc . Transgenetic studies argue that PrP Sc acts as a template upon which PrP C is refolded into a nascent PrP Sc molecule through a process facilitated by another protein. Miniprions generated in transgenic mice expressing PrP, in which nearly half of the residues were deleted, exhibit unique biological properties and should facilitate structural studies of PrP Sc . While knowledge about prions has profound implications for studies of the structural plasticity of proteins, investigations of prion diseases suggest that new strategies for the prevention and treatment of these disorders may also find application in the more common degenerative diseases.

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Mutation of the Prion Protein in Libyan Jews with Creutzfeldt–Jakob Disease

Cited by 247 publications

References 33 publications

The Role of Prion Peptide Structure and Aggregation in Toxicity and Membrane Binding

The Role of Prion Peptide Structure and Aggregation in Toxicity and Membrane Binding

Deletion of N-terminal Residues 23–88 from Prion Protein (PrP) Abrogates the Potential to Rescue PrP-deficient Mice from PrP-like Protein/Doppel-induced Neurodegeneration

Molecular characterization of proteolytic cleavage sites of the Pseudomonas syringae effector AvrRpt2

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