朊病毒中朊蛋白及朊蛋白现象

朊病毒病是一种由朊病毒侵染动物神经系统并引发神经退行性症状的传染性疾病。朊病毒是由正常朊蛋白PrP^C通过构象转化形成具蛋白酶抗性的异常朊蛋白PrP^Se的病原微生物。最新研究表明,朊蛋白通过构象转变形成新的功能分子的现象在生物界中普遍存在,并与正常生物功能密切相关。通过研究类朊蛋白现象可以有助于揭示朊病毒感染机制以及深化对生物遗传多样性的了解。     

Prion infection

The prion infection is a conversion of host encoded prion protein (PrP) from its cellular isoform PrPC into the pathological and infectious isoform PrPSc; the conversion process was investigated by in vitro studies using recombinant and cellular PrP and natural PrPSc. We present a brief summary of the results determined with our in vitro conversion system and the derived mechanistic models. We describe well characterized intermediates and precursor states during the conversion process, kinetic studies of spontaneous and seeded fibrillogenesis and the impact of the membrane environment.     

朊病毒疾病

朊病毒是一种蛋白性质的感染颗粒,它能引起动物的一类大脑功能紊乱疾病:可传染海绵样脑病(TSE)。本文就朊病毒、朊病毒引起的疾病、牛海绵样脑病(BSE)及BSE能否传给人类进行一些讨论。     

Prion proteostasis

Infectious amyloid forms of the release factor, Sup35, comprise the yeast prion [PSI⁺]. This protein-based unit of inheritance is an evolutionary capacitor able to release cryptic genetic variation during environmental stress and generate potentially beneficial phenotypes. Genetic data have uncovered a sophisticated proteostasis network that tightly regulates [PSI⁺] formation, propagation and elimination. Central to this network, is the AAA+ ATPase and protein disaggregase, Hsp104. Shifting the balance of the cytosolic Hsp70:Hsp40 chaperone machinery and associated nucleotide exchange factors also influences the [PSI⁺] prion cycle. Yet, a precise understanding of how these systems co-operate to directly modulate the protein folding events required for sustainable Sup35 prionogenesis has remained elusive. Here, we spotlight recent advances that begin to clarify this issue. We suggest that the Hsp70:Hsp40 chaperone machinery functions collectively as a rheostat that adjusts Hsp104’s basic prion-remodeling activities.     

Prion transmission

Prion diseases range from being highly infectious, for example scrapie and CWD which show facile transmission between susceptible individuals, to showing negligible horizontal transmission, such as BSE and CJD which are spread via food or iatrogenically respectively. Scrapie and CWD display considerable in vivo dissemination, with PrP^Sc and infectivity being found in a range of peripheral tissues. This in vivo dissemination appears to facilitate the recently reported excretion of prion through multiple routes such as from skin, faeces, urine, milk, nasal secretions, saliva and placenta. Furthermore, excreted scrapie and CWD agent is detected within environmental samples such as water and on the surfaces of inanimate objects. The cycle of ‘uptake of prion from the environment - widespread in vivo prion dissemination - prion excretion - prion persistence in the environment’ is likely to explain the facile transmission and maintenance of these diseases within wild and farmed populations over many years.     

朊病毒和朊病毒病研究进展

朊病毒病即海绵状脑病,是人和动物中的一类致死性中央神经系统疾病,近几年来在朊病毒病的致病机制及其诊断技术和防治策略方面取得了很大的研究进展.     

Prion neurodegeneration

Synaptic dysfunction is a key process in the evolution of many neurodegenerative diseases, with synaptic loss preceding the loss of neuronal cell bodies. In Alzheimer's, Huntington's, and prion diseases early synaptic changes correlate with cognitive and motor decline, and altered synaptic function may also underlie deficits in a number of psychiatric and neurodevelopmental conditions. The formation, remodelling and elimination of spines and synapses are continual physiological processes, moulding cortical architecture, underpinning the abilities to learn and remember. In disease, however, particularly in protein misfolding neurodegenerative disorders, lost synapses are not replaced and this loss is followed by neuronal death. These two processes are separately regulated, with mechanistic, spatial and temporal segregation of the death 'routines' of synapses and cell bodies. Recent insights into the reversibility of synaptic dysfunction in a mouse model of prion disease at neurophysiological, behavioral and morphological levels call for a deeper analysis of the mechanisms underlying neurotoxicity at the synapse, and have important implications for therapy of prion and other neurodegenerative disorders.     

与朊毒体相关的鱼类朊蛋白研究概况

疯牛病(mad cow disease),即牛传染性海绵状脑病(bovine transmissible spongiform encephalopathy,BSE)的俗称,是一种慢性消耗性、致死性、中枢神经系统退行性疾病。疯牛病被认为与朊毒体(Prion)有关,朊毒体是由正常朊蛋白(Prion protein,或者PrPC)发生构象改变后形成的异常蛋白(PrPSc)。疯牛病的发生引起了世界各国政府和科学界的高度重视,PrP的起源及其功能研究已成为研究热点。鱼类PrP相关蛋白的研究正在展开中,由于鱼类PrP相关蛋白与朊蛋白的结构相似,鱼类感染TSE类似病存在理论上的风险。本文全面地综述了疯牛病的概况、朊毒体的特性、朊毒体与哺乳动物朊蛋白、鱼类PrP相关蛋白(PrP1、PrP2和PrP3)及鱼类其他PrP相关蛋白的研究情况,为国内水生动物PrP相关蛋白研究提供参考。     

Prion reviewer acknowledgments

Prion is grateful for the ongoing support of its peer reviewers, who ensure that the submissions accepted for publication in Prion continue to be of the highest standard. We very much appreciate their time and the thoughtful reviews they provide. We would like to thank the following peer reviewers for their assistance in 2013:     

A Promiscuous Prion: Efficient Induction of [URE3] Prion Formation by Heterologous Prion Domains

The [URE3] and [PSI⁺] prions are the infections amyloid forms of the Saccharomyces cerevisiae proteins Ure2p and Sup35p, respectively. Randomizing the order of the amino acids in the Ure2 and Sup35 prion domains while retaining amino acid composition does not block prion formation, indicating that amino acid composition, not primary sequence, is the predominant feature driving [URE3] and [PSI⁺] formation. Here we show that Ure2p promiscuously interacts with various compositionally similar proteins to influence [URE3] levels. Overexpression of scrambled Ure2p prion domains efficiently increases de novo formation of wild-type [URE3] in vivo. In vitro, amyloid aggregates of the scrambled prion domains efficiently seed wild-type Ure2p amyloid formation, suggesting that the wild-type and scrambled prion domains can directly interact to seed prion formation. To test whether interactions between Ure2p and naturally occurring yeast proteins could similarly affect [URE3] formation, we identified yeast proteins with domains that are compositionally similar to the Ure2p prion domain. Remarkably, all but one of these domains were also able to efficiently increase [URE3] formation. These results suggest that a wide variety of proteins could potentially affect [URE3] formation.AMYLOID fibril formation is associated with numerous human diseases, including Alzheimer''s disease, type II diabetes, and the transmissible spongiform encephalopathies. Yeast prions provide a powerful model system for examining amyloid fibril formation in vivo. [URE3] and [PSI⁺] are the prion forms of the Saccharomyces cerevisiae proteins Ure2p and Sup35p, respectively (Wickner 1994). In both cases, prion formation is thought to result from conversion of the native protein into an inactive amyloid form (Glover et al. 1997; King et al. 1997; Taylor et al. 1999). Both proteins contain an N-terminal glutamine/asparagine (Q/N)-rich prion-forming domain (PFD) and a C-terminal functional domain (Ter-Avanesyan et al. 1993; Ter-Avanesyan et al. 1994; Masison and Wickner 1995; Liebman and Derkatch 1999; Maddelein and Wickner 1999). Sup35p contains an additional highly charged middle domain (M) that is not required either for prion formation or for normal protein function, but stabilizes [PSI⁺] aggregates (Liu et al. 2002).Amyloid fibril formation is thought to occur through a seeded polymerization mechanism. In vitro, amyloid fibril formation from native proteins is generally characterized by a significant lag time, thought to result from the slow rate of formation of amyloid nuclei; addition of a small amount of preformed amyloid aggregates (seeds) eliminates the lag time, resulting in rapid polymerization (Glover et al. 1997; Taylor et al. 1999; Serio et al. 2000).Despite considerable study, the mechanism by which amyloid seeds initially form is unclear. At least some of the amyloid proteins involved in human disease can interact with unrelated amyloidogenic proteins, resulting in cross-seeding and modulation of toxicity. Injecting mice with amyloid-like fibrils formed by a variety of short synthetic peptides promotes amyloid formation by amyloid protein A, a protein whose deposition is found in systemic AA amyloidosis (Johan et al. 1998). In yeast, [PSI⁺] and [PIN⁺], the prion form of the protein Rnq1p (Sondheimer and Lindquist 2000; Derkatch et al. 2001), both promote the aggregation of and increase toxicity of expanded polyglutamine tracts, like those seen in Huntington''s disease (Osherovich and Weissman 2001; Meriin et al. 2002; Derkatch et al. 2004; Gokhale et al. 2005; Duennwald et al. 2006); however, in Drosophila, [PSI⁺] aggregates reduce polyglutamine toxicity (Li et al. 2007). Thus, interactions between heterologous amyloidogenic proteins can influence amyloid formation both positively and negatively in vivo.A variety of interactions have been observed among the yeast prions. Under normal cellular conditions, efficient formation, but not maintenance, of [PSI⁺] requires the presence of [PIN⁺] (Derkatch et al. 2000). Overexpression of various Q/N-rich proteins can effectively substitute for [PIN⁺], allowing [PSI⁺] formation in cells lacking [PIN⁺] (Derkatch et al. 2001; Osherovich and Weissman 2001). In vitro and in vivo evidence suggest that the ability of [PIN⁺] to facilitate [PSI⁺] formation is the result of a direct interaction between Rnq1p aggregates and Sup35p (Derkatch et al. 2004; Bardill and True 2009; Choe et al. 2009). [PIN⁺] also increases the frequency of [URE3] formation, while [PSI⁺] inhibits [URE3] formation (Bradley et al. 2002; Schwimmer and Masison 2002).It is unclear whether the ability of Ure2p, Sup35p, and Rnq1p to cross-react is an intrinsic feature of all similar amyloidogenic proteins, or whether it has specifically evolved to regulate prion formation. There is debate as to whether yeast prion formation is a beneficial phenomenon, allowing for regulation of the activity of the prion protein (True and Lindquist 2000; True et al. 2004), or a deleterious event analogous to human amyloid disease (Nakayashiki et al. 2005). Either way, it is likely that interactions between the yeast prion proteins have specifically evolved, either to minimize the detrimental effects of amyloid formation or to regulate beneficial amyloid formation.For both Ure2p and Sup35p, the amino acid composition of the PFD is the predominant feature that drives prion formation. Scrambled versions of Ure2p and Sup35p (in which the order of the amino acids in the PFD was randomized while maintaining amino acid composition) are able to form prions when expressed in yeast as the sole copy Ure2p or Sup35p (Ross et al. 2004, 2005). To examine whether amino acid composition can similarly drive interactions between heterologous proteins, we tested whether the scrambled PFDs can interact with their wild-type counterparts to stimulate prion formation. When overexpressed, scrambled Ure2 PFDs promoted de novo prion formation by wild-type Ure2p, suggesting that the Ure2p PFD can promiscuously interact with compositionally similar PFDs during prion formation. When we searched the yeast proteome for proteins with regions of high compositional similarity to Ure2p, four of the top five proteins were able to efficiently stimulate [URE3] formation. However, there were limits to this promiscuity; overexpression of wild-type or scrambled Sup35 PFDs did not increase [URE3] levels. We propose that this ability to promiscuously interact may have evolved as a mechanism to regulate Ure2p activity and/or prion formation.     

Prion transmission: Prion excretion and occurrence in the environment

Prion diseases range from being highly infectious, for example scrapie and CWD, which show facile transmission between susceptible individuals, to showing negligible horizontal transmission, such as BSE and CJD, which are spread via food or iatrogenically, respectively. Scrapie and CWD display considerable in vivo dissemination, with PrP^Sc and infectivity being found in a range of peripheral tissues. This in vivo dissemination appears to facilitate the recently reported excretion of prion through multiple routes such as from skin, feces, urine, milk, nasal secretions, saliva and placenta. Furthermore, excreted scrapie and CWD agent is detected within environmental samples such as water and on the surfaces of inanimate objects. The cycle of “uptake of prion from the environment—widespread in vivo prion dissemination—prion excretion—prion persistence in the environment” is likely to explain the facile transmission and maintenance of these diseases within wild and farmed populations over many years.Key words: prion, PrP, excretion, secretion, transmission     

朊病毒,应改名

Prion是感染性蛋白质,能引发疯牛病等海绵状脑病。朊病毒是其被广泛沿用的中文译名．暗示prion是某种病毒。实际上,prion是蛋白质,不是病毒。朊病毒这个名字与实际不副,可能误导人们对prion的认识．也会误导对海绵状脑病的防治。因此,朊病毒不宜继续沿用下去,而应另起名实相副的新名。     

Prion diseases.

There have been remarkably rapid advances in the understanding of prion diseases over the past year. The controversial notion that the transmissible agent may be an abnormal isoform of a host-encoded protein, the prion protein, is now gaining wide acceptance. The conundrum of how a disease can both be inherited as an autosomal dominant condition and also be experimentally transmissible by inoculation is beginning to make sense.     

Prion protein glycosylation

The transmissible spongiform encephalopathies (TSE), or prion diseases are a group of transmissible neurodegenerative disorders of humans and animals. Although the infectious agent (the 'prion') has not yet been formally defined at the molecular level, much evidence exists to suggest that the major or sole component is an abnormal isoform of the host encoded prion protein (PrP). Different strains or isolates of the infectious agent exist, which exhibit characteristic disease phenotypes when transmitted to susceptible animals. In the absence of a nucleic acid genome it has been hard to accommodate the existence of TSE strains within the protein-only model of prion replication. Recent work examining the conformation and glycosylation patterns of disease-associated PrP has shown that these post-translational modifications show strain-specific properties and contribute to the molecular basis of TSE strain variation. This article will review the role of glycosylation in the susceptibility of cellular PrP to conversion to the disease-associated conformation and the role of glycosylation as a marker of TSE strain type.