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The Strain of Being a Prion Marston Exhibited a Number of Flints Which Mick F news and views To achieve the necessary sharper imaging, They show absorption spectra — corre- astronomers have resorted to a ‘shadow- sponding to their radiation being absorbed gram’technique,using a metal mask encoded by some intervening material between these with a pattern of holes to cast a shadow on a sources and INTEGRAL, meaning that large camera (Fig. 1). By correlating the they stand out only at ȍ-ray wavelengths. observed shadow with the known pattern in The absorbing material may be either the the coded mask, the position of the ȍ-ray accretion flow from a companion star, or a source can be pinpointed.The viability of the molecular cloud in which the source is 100 YEARS AGO technique was demonstrated by a pathfinder embedded. Now we know where these I happened to possess a small sample of a Russian–French telescope that flew on the objects are, follow-up observations using red deposit, coloured by iron, which is left by Russian GRANAT mission in 1989. other telescopes, such as ESA’s XMM– the water of the King’s Spring, at Bath. It Coded-mask telescopes need large Newton Observatory, will uncover their occurred to me that it might be worth while radiation-collecting areas to detect the faint nature more fully. to test this for radio-activity. The result was sources,and this in turn requires a big,heavy Over the coming years, INTEGRAL will to show that the deposit was markedly space observatory. For more than two make a complete census of the buried popu- active. On leaving it in the testing vessel decades, astronomers could only dream of lations of black holes and neutron stars in the (which was closed airtight) for a few days, the potential of such a ȍ-ray telescope for Milky Way. Exploiting its capabilities to the the activity was found to increase to several solving the mystery of our Galaxy’s ȍ-ray full, the observatory will be able to search times its initial value. This shows that the glow. ESA took up the challenge in the nearby galaxies for supermassive black holes deposit gives off an emanation freely, even mid-1990s and led the development of the buried in their centres, pick up ȍ-ray bursts without heat. Experiments were then made INTEGRAL observatory. In October 2002, and detect the radioactive decay of newborn to test the rate of decay of this emanation. It it was launched on a Russian Proton rocket. elements in the fires of exploding super- proved to be identical with the rate of decay The INTEGRAL observations reported novae. The Universe will appear to be a of the emanation of radium… The presence by Lebrun et al.reveal many dozens of very different place when viewed clearly of radium in the Bath water and deposits is sources, most of them quite faint. The sum with ȍ-ray eyes. ■ of special interest because of the occurrence of their ȍ-radiation matches the ȍ-ray flux Nicholas White is at the Laboratory for High Energy of helium in the gas which arises from the previously attributed to the diffuse glow. Astrophysics, NASA Goddard Space Flight Center, spring… There can be little doubt that the Many of the newly discovered sources seem Greenbelt, Maryland 20771, USA. helium owes its origin to the same store of to be either black holes or neutron stars. e-mail: [email protected] radium that supplies the water. From Nature 17 March 1904. Cell biology 50 YEARS AGO At a meeting of the Geological Society held at Burlington house on February 24, Mr. A. T. The strain of being a prion Marston exhibited a number of flints which Mick F. Tuite he had attempted to stain with chromic acid or potassium dichromate in order to assist Prions are remarkable infectious agents associated with certain brain appreciation of the condition of the Piltdown diseases. But they also occur in fungi, experiments with which now flint recently described by Drs. Oakley and provide plausible answers to some critical questions about prion biology. Weiner (Nature, December 12, 1953). Mr. Marston pointed out that though some types widely (but not universally) accepted bovine spongiform encephalopathy in of these flints would not stain at all, others dogma about the agents known as cows4.Prion proteins have also been linked became deeply stained. In the latter case, A prions is that they are protein-based with stable, heritable traits in two fungi however, the stain was very difficult to entities that are self-perpetuating,‘infectious’ (Saccharomyces cerevisiae and Podospora remove. As the stain on the Piltdown flint and devoid of any transmissible nucleic acids. anserina), although none of the four known had apparently been easily removed by acid, Yet despite intensive research into this ‘pro- fungal prions can be considered ‘disease- Mr. Marston queried whether it had indeed tein only’ hypothesis1,two crucial challenges causing’ — some may in fact be beneficial been artificially produced, and also inquired have remained unanswered. Can infectivity to the host5. whether there was any possibility that traces with purified prion protein be demonstrated? King and Diaz-Avalos2,and Tanaka et al.3, of chromium might exist naturally in the And how can different prion ‘strains’ be have exploited the prion properties of the ferruginous Piltdown gravels. Dr. Oakley then generated without any underlying change in Sup35p protein of S. cerevisiae.Sup35p is an exhibited specimens of flint from Piltdown, the amino-acid sequence of the prion protein essential factor required by the protein-syn- and described tests that had been made on or in the genetic make-up of the host? Papers thesizing organelles— the ribosomes — to all the flints illustrated in the original paper in this issue by King and Diaz-Avalos2 and terminate synthesis of a polypeptide chain. by C. Dawson and A. Smith Woodward. All Tanaka et al.3 (pages 319 and 323) address Cells in which most of the Sup35p protein these flints had a ferruginous stain which these challenges. They provide the most molecules have been converted to their prion was easily removed by acid, in contrast to dramatic demonstration to date of the valid- form ([PSI+] cells) are defective in this the other ‘natural’ flints from the Piltdown ity of the protein-only hypothesis. crucial termination phase. area collected at the same time… Dr. Oakley Infection of the host by a prion can, over [PSI+] cells can be readily detected in a believed that the illustrated flints had been time, lead to the replication and subsequent population of ‘normal’ genetically marked stained artificially with a ferruginous transmission of an aggregated fibrous form [psiǁ] cells by a simple screen involving cell solution, and in one case a chromic solution of the infectious protein known as an amy- colour and protein analysis (Fig. 1, overleaf). had also been used in order to make the flint loid. In mammals, the only known prion Using this screen, King and Diaz-Avalos,and less red, and so resemble more closely the protein (PrP) is associated with a group of Tanaka et al., independently developed what ‘natural’ flints. neurodegenerative diseases that include are essentially protein-only transformation From Nature 20 March 1954. Creutzfeldt–Jakob disease in humans and systems and used them to demonstrate that NATURE | VOL 428 | 18 MARCH 2004 | www.nature.com/nature 265 © 2004 Nature Publishing Group news and views Figure 1 Prion behaviour in the yeast S. cerevisiae. different conformers each generates different [psi–] + Tell-tale colony colours are shown, along with an [PSI ] variants, both groups firmly establish indication of the amount of Sup35p protein in the link. Furthermore, these conformational soluble (S lane) or aggregated (P lane) form. differences are propagated in vivo3. [psiǁ] yeast cells contain a soluble form of the At least for yeast prions, attention can SP Sup35p protein. Such cells fail to suppress the now turn to the baffling matter of how the ade1-14 mutation, because of effective amyloid form is propagated, thereby ensur- translation termination, leading to red colonies ing stable transmission to daughter cells. being formed on agar plates. Two different [PSI+] Two basic mechanisms, known as template- strains can be generated de novo; they differ not directed refolding and seeded nucleation, only in the conformation of Sup35p, but also have been widely touted11.But what is the + [PSI ] in the extent to which the Sup35p protein is molecular nature of the propagating unit generation + and aggregated. In the ‘strong’ [PSI ] strain, more (or seed)? Is it a conformationally altered propagation than 95% of the Sup35p protein is in the non- monomeric form of the protein,or the highly functional, aggregated fraction (lane P). These aggregated amyloid form? These questions cells produce white colonies because translation can now be tackled using the new prion termination is impaired and the ade1-14 transformation assays, and there are already mutation is suppressed. In the ‘weak’ [PSI+] candidates. For example, high-molecular- + strain, a significant level of Sup35p is also seen weight Sup35p aggregates in [PSI ] cells can ‘Strong’ strain ‘Weak’ strain in the soluble fraction (lane S). The ‘weak’ be broken down into smaller, detergent- strain therefore shows a partial restoration of insoluble Sup35p-based polymers, and the + translation termination and concomitantly less size of the polymer depends on the [PSI ] efficient suppression of the ade1-14 mutation strain12.Could these detergent-insoluble giving pink colonies. Once a particular strain polymers be the active seeds? We now have a SP SP has been generated, it is stably replicated in powerful way of approaching the remaining that conformation. mysteries of prion propagation in yeast, and one that could equally be applied to the cells [psiǁ] cells can be ‘infected’ — that is, turned process (Fig.
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