RESOLUTION OF STRAWBERRY VIRUS COMPLEXES

Strawberry virus 4 produces vein chlorosis and necrosis on strawberry (var. Royal Sovereign) and slight chlorotic spotting on wild strawberry ( Fragaria vesca L.). No vector is known. Virus 5 produces leaf curling and vein necrosis on Royal Sovereign and F. vesca. It is transmitted by strawberry aphids ( Pentatrichopus fragaefolii Cock.) which have fed on an infected plant for 1 hr. or more and persists for about 1 hr. in the vector.
The names strawberry mottle, mild yellow-edge, crinkle, vein chlorosis and leaf-curl virus are proposed for strawberry viruses 1, 2, 3, 4 and 5 respectively.     

A spontaneous mutation in the movement protein gene of brome mosaic virus modulates symptom phenotype in Nicotiana benthamiana.

Brome mosaic virus (BMV) is a positive-strand RNA virus with a multipartite genome that causes symptomless infection in Nicotiana benthamiana. We have isolated and characterized a strain of BMV that produced uniform vein chlorosis in systemically infected N. benthamiana. Analysis of pseudorecombinants constructed by exchanging RNA 1 and 2 and RNA 3 components between wild-type (non-symptom-inducing) and vein chlorosis-inducing strains of BMV indicated that the genetic determinant for the induction of the chlorotic phenotype is located on RNA 3. Sequence analysis of progeny RNA 3 recovered from symptomatic N. benthamiana plants revealed that vein chlorosis is due to the single nucleotide transition 887G-->887A, which changes the codon for Val-266 to Ile-266 in the movement protein gene. The mutation had no detectable effect on the accumulation of virus in either inoculated or systematically infected leaves of N. benthamiana. The vein chlorosis phenotype is the manifestation of the substitution of Ile-266 for Val-266 in the movement protein gene, since additional alterations in this region (a silent mutation, i.e., 887GUU889-->GUC, and an alteration of valine to phenylalanine, i.e., 887GUU889-->887UUU889) resulted in symptomless infections on N. benthamiana. The modulation of the symptom phenotype by the substitution of Ile-266 for Val-266 is specific for N. benthamiana, since neither movement nor the symptom phenotype in barley plants was affected.     

The peripheral nervous system and the pathogenesis of prion diseases

Prion diseases are inevitably fatal neurodegenerative conditions which affect humans and a wide variety of animals. Unlike other protein aggregation diseases such as Alzheimer's, Parkinson's, and polyglutamine repeat diseases, prion diseases are unique in that they are transmissible. Therefore, prion diseases are also called transmissible spongiform encephalopathies. A number of prion diseases are caused by peripheral uptake of the infectious agent. In order to reach their target, the central nervous system, prions enter their host, accumulate and replicate in lymphoid organs, and eventually spread to the central nervous system via peripheral nerves. Once the agent has reached the central nervous system, disease progression is rapid, resulting in neurodegeneration and death. In this article, we review the state of knowledge on the routes of neuroinvasion used by the infectious agent in order to gain access to the central nervous system upon entry into extracerebral sites.     

Bridging the gap between molecular epidemiologists and evolutionists

Molecular epidemiology designates the various molecular methods that aim to identify the relevant units of analysis of pathogens involved in transmissible diseases: species, subspecies, strains, clones and genes of interest. It is frequently based on an empirical approach. I advocate that evolutionary concepts enrich this discipline considerably and should be considered as an integral part. In turn, the experience and questioning of field experts are crucial to evolutionists who use transmissible diseases as models. A molecular epidemiology aim gives evolutionary studies a practical goal, putting a stop to approaches that are overly speculative.     

Molecular aspects of disease pathogenesis in the transmissible spongiform encephalopathies

The transmissible spongiform encephalopathies (TSE), or prion diseases, are a group of rare, fatal, and transmissible neurodegenerative diseases of mammals for which there are no known viral or bacterial etiological agents. The bovine form of these diseases, bovine spongiform encephalopathy (BSE), has crossed over into humans to cause variant Creutzfeldt-Jakob disease. As a result, BSE and the TSE diseases are now considered a significant threat to human health. Understanding the basic mechanisms of TSE pathogenesis is essential for the development of effective TSE diagnostic tests and anti-TSE therapeutic regimens. This review provides an overview of the molecular mechanisms that underlie this enigmatic group of diseases.     

Subclinical prion infection

Prion diseases are transmissible neurodegenerative disorders that include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle and Creutzfeldt–Jakob disease (CJD) in humans. The principal component of the infectious agent responsible for these diseases appears to be an abnormal isoform of the host-encoded prion protein (PrP), designated PrP^Sc. Prion diseases are transmissible to the same or different mammalian species by inoculation with, or dietary exposure to, infected tissues. Although scrapie in sheep has been recognized for over 200 years, it is the recent epidemic of BSE that has centred much public and scientific attention on these neurodegenerative diseases. The occurrence of variant CJD in humans and the experimental confirmation that it is caused by the same prion strain as BSE has highlighted the need for intensive study into the pathogenesis of these diseases and new diagnostic and therapeutic approaches. The existence and implications of subclinical forms of prion disease are discussed.     

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.     

Tobacco yellow vein,a virus dependent on assistor viruses for its transmission by aphids*

Tobacco yellow vein, a disease found in Malawi, is caused by a combination of two viruses transmitted in the persistent manner by aphids. One component, tobacco yellow vein virus (TYVV) is manually transmissible, but aphids transmit it only from plants also containing the other (assistor) component, which is not manually transmissible. Aphids also transmit TYVV from plants containing either of two other assistor viruses - tobacco vein-distorting and groundnut rosette assistor. A virulent isolate of TYVV infected Soja max, Arachis hypogaea and several solanaceous species. It infected plants already containing tobacco mottle or groundnut rosette viruses but not those containing a mild isolate of TYVV.     

Amyloids, prions and the inherent infectious nature of misfolded protein aggregates

Misfolded aggregates present in amyloid fibrils are associated with various diseases known as "protein misfolding" disorders. Among them, prion diseases are unique in that the pathology can be transmitted by an infectious process involving an unprecedented agent known as a "prion". Prions are infectious proteins that can transmit biological information by propagating protein misfolding and aggregation. The molecular mechanism of prion conversion has a striking resemblance to the process of amyloid formation, suggesting that misfolded aggregates have an inherent ability to be transmissible. Intriguing recent data suggest that other protein misfolding disorders might also be transmitted by a prion-like infectious process.     

Genesis of mammalian prions: from non-infectious amyloid fibrils to a transmissible prion disease

The transmissible agent of prion disease consists of a prion protein in its abnormal, β-sheet rich state (PrP(Sc)), which is capable of replicating itself according to the template-assisted mechanism. This mechanism postulates that the folding pattern of a newly recruited polypeptide chain accurately reproduces that of a PrP(Sc) template. Here we report that authentic PrP(Sc) and transmissible prion disease can be generated de novo in wild type animals by recombinant PrP (rPrP) amyloid fibrils, which are structurally different from PrP(Sc) and lack any detectable PrP(Sc) particles. When induced by rPrP fibrils, a long silent stage that involved two serial passages preceded development of the clinical disease. Once emerged, the prion disease was characterized by unique clinical, neuropathological, and biochemical features. The long silent stage to the disease was accompanied by significant transformation in neuropathological properties and biochemical features of the proteinase K-resistant PrP material (PrPres) before authentic PrP(Sc) evolved. The current work illustrates that transmissible prion diseases can be induced by PrP structures different from that of authentic PrP(Sc) and suggests that a new mechanism different from the classical templating exists. This new mechanism designated as "deformed templating" postulates that a change in the PrP folding pattern from the one present in rPrP fibrils to an alternative specific for PrP(Sc) can occur. The current work provides important new insight into the mechanisms underlying genesis of the transmissible protein states and has numerous implications for understanding the etiology of neurodegenerative diseases.     

An Emerging Concept of Prion Infections as a Form of Transmissible Cerebral Amyloidosis

Proteins are a major constituent of cells with specific biological functions. Besides the primary structure that is simply the sequence of amino acids that comprise a protein, the secondary structure represents the first step of folding defining its general conformation. The biological functions of proteins are directly dependent on the acquisition of their conformation. The same protein can have different stable states, which may participate with different functions in the cell. The amyloid diseases comprise Alzheimer’s and Parkinson’s diseases, type II diabetes mellitus and systemic amyloidosis. Amyloid fibers are insoluble, resistant to proteolysis and show an extremely high content of β-sheet, in a very similar structure to the one observed among prion rods, associated to the transmissible spongiform encephalopathies. All these diseases are “infectious” in the sense that misfolded β-sheeted conformers formed in a nucleation process in which preformed metastable oligomer acts as a seed to convert a normal isoform into an abnormal protein with a misfolded conformation. Only prion infections have a proven infectivity in a microbiological sense; some recent observations, however, detected the transmissibility of systemic amyloidosis by a prion-like mechanism among mice. Prions diseases and amyloidosis present many similar aspects of the so-called conformational diseases; according to this interpretation the prion infections could be considered as a form of transmissible cerebral amyloidosis.     

Birth of a prion: spontaneous generation revisited

The proposal that the transmissible agent in prion diseases can be a conformationally altered host protein that multiplies by autocatalytic conversion has gained wide acceptance. Recent work shows that the agent, the prion, can be replicated in a cell-free system, that it can be generated de novo, and that the strain-specific properties of prions are encoded by conformational variations of the underlying protein.     

PrP的胞内运输与朊病毒病

朊病毒病,即传染性海绵状脑病（transmissible spongiform encephalopathies,TSEs）,是一类致死性的神经退行性疾病,存在散发性、感染性和遗传性3种形式。在朊病毒病的病理过程中,细胞正常朊蛋白PrPc（cellular PrP）转化为异常构象的PrP^Sc（scrapie PrP）是至关重要的,但是朊病毒的增殖如何导致神经元凋亡仍不清楚。PrPc的胞内运输在朊病毒病中发挥重要作用,朊病毒感染后PrP^C转化为PrP^Sc,及遗传性朊病毒病中PrP突变可能影响PrP的生物合成、亚细胞定位及转运过程,通过干扰PrP^C的正常功能或产生毒性中间体而导致神经系统病变。现对近年来关于PrP胞内运输在朊病毒病中的作用进行综述。     

Prions and prion diseases: fundamentals and mechanistic details

Prion diseases, often called transmissible spongiform encephalopathies (TSEs), are infectious diseases that accompany neurological dysfunctions in many mammalian hosts. Prion diseases include Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy (BSE, "mad cow disease") in cattle, scrapie in sheep, and chronic wasting disease (CWD) in deer and elks. The cause of these fatal diseases is a proteinaceous pathogen termed prion that lacks functional nucleic acids. As demonstrated in the BSE outbreak and its transmission to humans, the onset of disease is not limited to a certain species but can be transmissible from one host species to another. Such a striking nature ofprions has generated huge concerns in public health and attracted serious attention in the scientific communities. To date, the potential transmission ofprions to humans via foodbome infectiorn and iatrogenic routes has not been alleviated. Rather, the possible transmission of human to human or cervids to human aggravates the terrifying situation across the globe. In this review, basic features about prion diseases including clinical and pathological characteristics, etiology, and transmission of diseases are described. Based on recently accumulated evidences, the molecular and biochemical aspects of prions, with an emphasis on the molecular interactions involved in prion conversion that is critical during prion replication and pathogenesis, are also addressed.     

An Emerging Concept of Prion Infections as a Form of Transmissible Cerebral Amyloidosis

Proteins are a major constituent of cells with specific biological functions. Besides the primary structure that is simply the sequence of amino acids that comprise a protein, the secondary structure represents the first step of folding defining its general conformation. The biological functions of proteins are directly dependent on the acquisition of their conformation. The same protein can have different stable states, which may participate with different functions in the cell.The amyloid diseases comprise Alzheimer''s and Parkinson''s diseases, type II diabetes mellitus and systemic amyloidosis. Amyloid fibers are insoluble, resistant to proteolysis and show an extremely high content of β-sheet, in a very similar structure to the one observed among prion rods, associated to the transmissible spongiform encephalopathies. All these diseases are “infectious” in the sense that misfolded β-sheeted conformers formed in a nucleation process in which preformed metastable oligomer acts as a seed to convert a normal isoform into an abnormal protein with a misfolded conformation. Only prion infections have a proven infectivity in a microbiological sense; some recent observations, however, detected the transmissibility of systemic amyloidosis by a prion-like mechanism among mice. Prion diseases and amyloidosis present many similar aspects of the so-called conformational diseases; according to this interpretation the prion infections could be considered as a form of transmissible cerebral amyloidosis.Key Words: conformational diseases, prion diseases, amyloidoses     

Stressing out the ER: a role of the unfolded protein response in prion-related disorders

Transmissible Spongiform Encephalopathies are fatal and infectious neurodegenerative diseases characterized by extensive neuronal apoptosis and the accumulation of an abnormally folded form of the cellular prion protein (PrP), denoted PrP(SC). Compelling evidence suggests the involvement of several signaling pathways in prion pathogenesis, including proteasome dysfunction, alterations in the protein maturation pathways and the unfolded protein response. Recent reports indicate that endoplasmic reticulum stress due to the PrP misfolding may be a critical factor mediating neuronal dysfunction in prion diseases. These findings have applications for developing novel strategies for treatment and early diagnosis of transmissible spongiform encephalopathies and other neurodegenerative diseases.     

朊病毒疾病的诊断技术

朊病毒疾病即海绵状脑病,是人的动物中的一类致死性中央神经系统疾病,介绍了朊病毒疾病的诊断技术,病理诊断,基因诊断,免疫诊断和血液检测。     

Genesis of tramsmissible protein states via deformed templating

Prion replication occurs via a template-assisted mechanism, which postulates that the folding pattern of a newly recruited polypeptide chain accurately reproduces that of a template. The concept of prion-like template-assisted propagation of an abnormal protein conformation has been expanded to amyloidogenic proteins associated with Alzheimer, Parkinson, Huntington diseases, amyotrophic lateral sclerosis and others. Recent studies demonstrated that authentic PrP^Sc and transmissible prion disease could be generated in wild type animals by inoculation of recombinant prion protein amyloid fibrils, which are structurally different from PrP^Sc and lack any detectable PrP^Sc particles. Here we discuss a new replication mechanism designated as “deformed templating,” according to which fibrils with one cross-β folding pattern can seed formation of fibrils or particles with a fundamentally different cross-β folding pattern. Transformation of cross-β folding pattern via deformed templating provides a mechanistic explanation behind genesis of transmissible protein states induced by amyloid fibrils that are considered to be non-infectious. We postulate that deformed templating is responsible for generating conformationally diverse amyloid populations, from which conformers that are fit to replicate in a particular cellular environment are selected. We propose that deformed templating represents an essential step in the evolution of transmissible protein states.