Experimental Transmission of a Kuru-like Syndrome to Chimpanzees

Gajdusek, D. C.; Gibbs, Clarence J.; Alpers, Michael P.

doi:10.1038/209794a0

Cited by 740 publications

(298 citation statements)

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“…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).…”

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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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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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“…Although CJD, GSS and FFI are rare diseases, found only once per 106-107 individuals per year, kuru assumed epidemic proportions in the first decades of this century in Papua New Guinea. Inoculation studies by Gajdusek and his colleagues resulted in the transmission of kuru to chimpanzees [2,3] and by now all human prion diseases have been transmitted to experimental animals, including the mouse. It is believed that kuru was propagated by ritual cannibalism [4,5] and may have originated with the consumption of the remains of a CJD sufferer.…”

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Molecular biology of transmissible spongiform encephalopathies

1996

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The prion, the transmissible agent that causes spongiform encephalopathies such as serapie, bovine spongiform encephalopathy (BSE) and Creutzfeldt-Jakob disease, is believed to be devoid of nucleic acid and identical with PrP so, a modified form of the normal host protein PrP ¢ which is encoded by the single cop~v gene Prnp. The 'protein only" hypothesis proposes that PrP ~c, when introduced into a normal host, causes the conversion of PrP c into prpS~; it therefore predicts that an animal devoid of PrP c should be resistant to prion diseases. We generated homozygous Prnp °1° ('PrP knockout') mice and showed that, after inoculation with prions, they remained free of scrapie for at least 2 years while wild-type controls all died within 6 months. There was no propagation of prions in the Prnp °t° animals. Surprisingly, heterozygous Prnp °t+ mice, which express PrP c at about half the normal level, also showed enhanced resistance to scrapie disease despite high levels of infectious agent and PrP ~c in the brain early on. After introduction of murine PrP transgenes Prnp °t° mice became highly susceptible to mouse but not to hamster prions, while the insertion of Syrian hamster PrP transgenes rendered them susceptible to hamster but to a much lesser extent to mouse prions. These complementation experiments paved the way to the application of reverse genetics. We have prepared animals transgenic for genes encoding PrP with amino terminal deletions of various lengths and have found that PrP lacking 48 amino proximal amino acids, which comprise four of the five octa repeats of PrP, is still biologically active.

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“…In response to his insight, Gajdusek replied that "we are pursuing the matter of possible infectious etiology extensively", and took up Hadlow's recommendation to hold small laboratory rodents and (especially) monkeys for longer periods of observation than had been done previously. He also renewed attempts to obtain optimal tissue for inoculation from rapidly autopsied kuru (Gajdusek, 1993 comments preceded the discovery of kuru transmissibility by more than 4 years (Gajdusek et al, 1966;Gibbs, 1993 …”

Section: Kuru Etiologymentioning

confidence: 99%