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Creutzfeldt–Jakob disease (CJD) subtypes are difficult to identify due to the heterogeneity of the clinical phenotype, and early accurate identification of sporadic CJD (sCJD) subtypes aids prognosis prediction. Currently, the diagnosis of sCJD subtypes is mainly based on brain tissue biopsy or autopsy. In this report, we present a case of confirmed sCJD initially presenting as insomnia. We described detailed information including clinical, electroencephalographic, polysomnographic, positron emission tomography-computed tomographic and other neuroimaging findings, cerebrospinal fluid biomarkers, skin tissue biopsy and whole blood PRNP gene sequencing in this patient. An extensive literature search was performed in order to better understand the diagnosis of various sCJD subtypes, particularly the thalamic form, sCJDMM2 (also known as sporadic fatal insomnia). Our study highlights sporadic fatal insomnia as a differential diagnosis of sCJD., Video abstract Point your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use: https://youtu.be/jCqVlf1vqVU

Scrapie is a transmissible spongiform encephalopathy caused by prions and leads to neurodegeneration in the Central Nervous System (CNS) of sheep and goats. Genetic resistance/susceptibility to scrapie is well studied and it is known that the variations of 136th, 154th and 171st codons at the ovine PRNP gene have a major effect on the development of the disease. Many studies demonstrated that selection for PRNP genotypes has not influenced other performance traits, nevertheless, there is a knowledge gap about the possible link between the PRNP gene and the status of the other important diseases that affect the sheep population worldwide. in the present study, we tested whether there is an association between scrapie-related PRNP genotypes and fecal egg count (FEC) of gastrointestinal nematodes in seven adult Turkish sheep breeds. For this purpose, FEC scores of studied sheep (n = 253) were determined and the same animals were genotyped for the PRNP gene. Finally, an association analysis was performed for scrapie resistant (ARR), susceptible (VRQ), and wild-type (ARQ) haplotypes. Based on our statistical analysis, it is concluded that PRNP genotypes have no positive or negative effect on the FEC scores of adult sheep., Republic of Turkey Ministry of Agriculture and Forestry, General Directorate of Agricultural Research and Policies [TAGEM/HAYSUD/15/A01/P02/02-02], This research has been funded by the Republic of Turkey Ministry of Agriculture and Forestry, General Directorate of Agricultural Research and Policies (Project number: TAGEM/HAYSUD/15/A01/P02/02-02).

In sheep, scrapie is a fatal neurologic disease that is caused by a misfolded protein called a prion (designated PrPSc). The normal cellular prion protein (PrPC) is encoded by an endogenous gene, PRNP, that is present in high concentrations within the CNS. Although a broad range of functions has been described for PrPC, its entire range of functions has yet to be fully elucidated. Accumulation of PrPSc results in neurodegeneration. The PRNP gene has several naturally occurring polymorphisms, and there is a strong correlation between scrapie susceptibility and PRNP genotype. The cornerstone of scrapie eradication programs is the selection of scrapie-resistant genotypes to eliminate classical scrapie. Transmission of classical scrapie in sheep occurs during the prenatal and periparturient periods when lambs are highly susceptible. Initially, the scrapie agent is disseminated throughout the lymphoid system and into the CNS. Shedding of the scrapie agent occurs before the onset of clinical signs. In contrast to classical scrapie, atypical scrapie is believed to be a spontaneous disease that occurs in isolated instances in older animals within a flock. The agent that causes atypical scrapie is not considered to be naturally transmissible. Transmission of the scrapie agent to species other than sheep, including deer, has been experimentally demonstrated as has the transmission of nonscrapie prion agents to sheep. The purpose of this review is to outline the current methods for diagnosing scrapie in sheep and the techniques used for studying the pathogenesis and host range of the scrapie agent. Also discussed is the US scrapie eradication program including recent updates.

Creutzfeldt-Jakob disease (CJD) is an uncommon neurodegenerative disorder with an incidence of 1 per 1,000,000 in humans per year, typically characterized by rapidly progressive dementia, ataxia, myoclonus and behavioral changes. Genetic prion diseases, which develop due to a mutation in the prion protein gene (PRNP), account for an estimated 10 to 15% of all CJD cases. Familial CJD is transmitted with an autosomal dominant inheritance pattern with high penetrance. Worldwide, the most common mutation is E200K (glutamate to lysine). We report four families with CJD assisted in Neuquén Hospital in 2018. Three of the four index cases had family history of neurological and psychiatric illness, though data was not taken into consideration at the moment of evaluation of the new cases. The most significant data recorded for a genetic consultation was when the problem had started, and it was required by a neurologist. The initial symptoms were persistent insomnia and depression with poor response to habitual psychiatric medication. Impoverishment is fast with visual disorder, myoclonias, ataxia, dementia and loss of language. Pedigree analysis allowed the identification of 144persons with the gene potential, who can develop the disease at any time in their adulthood. In all cases, mutation E200K was identified. There is a region of increased frequency of CJD. There must be suspicion on patients with neuropsychiatric symptoms and suspected family history(familiar background). Finding of the mutation confirms the diagnosis in patients and allows the identification on pre-symptomatic individuals. Challenge is posed on gene advice and to avoid iatrogenic disorder transmission. Key words: Familial Creutzfeldt-Jakob Syndrome, PRNP gene, E200K, CJD in Patagonia

The Caprine Prion Protein (PrP) gene polymorphism in three different native Indian goat populations of Southern Odisha, namely Ganjam (a registered breed of India), Ghumusari and Raighar was studied. The 876 bp amplified segment of PrP gene contains full length coding sequence of 771 bp. In Ganjam and Ghumusari goats, any difference of nucleotide sequence was not identified. However, the comparison of nucleotide sequences of Raighar goats and goats of other locality revealed a change in nucleotide at five different positions (G190A, G724A, A727T, C775G and C800T) which includes two non-synonymous nucleotide changes. The non-synonymous nucleotide change resulted a change in amino acid at two different positions (Ser234Cys and Lys246Phe) in mature polypeptide which were not reported earlier and therefore, considered as novel. On the basis of these variants of PrP gene phylogenetic tree was constructed which showed that Ganjam and Raighar goats appeared in different clade. Since any occurrence of Scrapie infection in goats of Odisha was not reported, it can be proposed that these changes in amino acid may be responsible as resistance allele.

Background Creutzfeldt–Jakob disease (CJD), the most common prion disease in humans, is primarily known for its adverse neurological impact and inevitable mortality. Data regarding myocardial involvement in CJD are scarce. Case summary A 54-year-old female patient, presented with progressive effort dyspnoea, was diagnosed with unexplained non-ischaemic cardiomyopathy. An extensive cardiac work-up including cardiac magnetic resonance imaging (MRI) did not reveal any underlying aetiology. Simultaneously, the patient developed involuntary limb movements and progressive cognitive decline. Thalamic high-signal abnormalities on diffusion-weighted images were apparent on brain MRI. Based on these findings, she was subsequently referred to a neurology department, where she suddenly died the day after her admission. Brain autopsy demonstrated spongiform encephalopathy. A genetic analysis performed to her son revealed a mutation in the PRNP gene; all of these were consistent with CJD. Discussion This case describes the clinical association of CJD and cardiomyopathy and the diagnosis prion-induced cardiomyopathy by exclusion. It is not inconceivable that the coexistence of these two clinical entities may be related to genetic expression and contemporaneously deposition of infectious prions in myocardial muscle and brain tissue. Awareness of this possible association could be of important public-safety concern, and merits further collaborative cardiac-neurological work-up to elucidate this phenotype among patients with unexplained cardiomyopathy with neurological symptoms that resemble CJD.

Chronic wasting disease (CWD) is caused by prions, infectious proteinaceous particles, PrPCWD. We sequenced the PRNP gene of 2,899 white-tailed deer (WTD) from Illinois and southern Wisconsin, find...

Chronic wasting disease is a fatal, horizontally transmissible prion disease of cervid species that has been reported in free-ranging and farmed animals in North America, Scandinavia, and Korea. Like other prion diseases, CWD susceptibility is partly dependent on the sequence of the prion protein encoded by the host’s PRNP gene; it is unknown if variations in PRNP have any meaningful effects on other aspects of health. Conventional diagnosis of CWD relies on ELISA or IHC testing of samples collected post-mortem, with recent efforts focused on antemortem testing approaches. We report on the conclusions of a study evaluating the role of antemortem testing of rectal biopsies collected from over 570 elk in a privately managed herd, and the results of both an amplification assay (RT-QuIC) and conventional IHC among animals with a several PRNP genotypes. Links between PRNP genotype and potential markers of evolutionary fitness, including pregnancy rates, body condition, and annual return rates were also examined. We found that the RT-QuIC assay identified significantly more CWD positive animals than conventional IHC across the course of the study, and was less affected by factors known to influence IHC sensitivity – including follicle count and PRNP genotype. We also found that several evolutionary markers of fitness were not adversely correlated with specific PRNP genotypes. While the financial burden of the disease in this herd was ultimately unsustainable for the herd owners, our scientific findings and the hurdles encountered will assist future CWD management strategies in both wild and farmed elk and deer.

Genetic Creutzfeldt–Jakob disease (gCJD) is characterized by mutations in the PRNP gene and represents approximately 10–15% of the human prion diseases. Here, we report a 42-year-old Chinese man who was diagnosed with gCJD. The patient had a rare mutation in codon 196 (E196A) of PRNP leading to an exchange of amino acid from glutamic acid (E) to alanine (A). The polymorphism of codon 129 in the patient was methionine homozygote. His mother and daughter are asymptomatic carriers of the same mutation. The clinical manifestations were similar to those of sporadic CJD. 14-3-3 protein was positive in cerebrospinal fluid, and there were sharp slow complex waves in electroencephalography and ribbon-like signals on magnetic resonance imaging (MRI). The main complaints of patient changed from visual space and visual colour to psychotic symptoms with enhanced high signal intensity on the occipital and frontal cortices on MRI. We compared the clinical characteristics of the current patient with those of previously reported Chinese patients with other gCJD of E196A mutation to summarize the common features of E196A gCJD.

Cellular Prion proteins have a wide variety of function from the birth of a cell to its programmed death. Prion protein can be the cause for a number of lethal animal and human diseases when misfolded. Furthermore, prion infection is transmissible. Polymorphisms of prion gene at different loci are associated with prion diseases development, the onset of symptoms and incubation period. Indel polymorphism in the promoter region of PRNP gene is found to be accoaited to BSE in cattle while the haplotype ARR at positions 136,154 and 171 is resistant to scrapie in sheep. Taking into account the severity of prion disease and its potential entrance to the food chain, genetic and clinical studies continued to be conducted in a different course of time in many countries.

The clinical characteristics of genetic Creutzfeldt-Jakob disease (gCJD) with a V180I mutation in the PRNP gene (V180I gCJD) are unique: elderly-onset, gradual progression, sporadic fashion, and cortical oedematous hyper-intensity on diffusion-weighted MRI (DW-MRI). This phenotype may become a potential target of future clinical therapeutic trials. The average disease duration of V180I gCJD patients is 23–27 months; however, considerably long-term survivors are also reported. The factors influencing survival and the clinicopathological characteristics of long-term survivors remain unknown. Herein, we report clinicopathological findings of a long-term survivor of V180I gCJD. A 78-year old woman was admitted to our hospital due to dementia and left hand tremor approximately 1.5 months after symptom onset. Neurological examination revealed dementia, frontal signs, and left hand tremor at admission. She had no family history of dementia or other neurological disease. DW-MRI revealed cortical oedematous hyper-intensities in the bilateral frontal lobes and the right temporal and parietal lobes. PRNP gene analysis indicated a V180I mutation with methionine homozygosity at codon 129. The symptoms gradually progressed, and she died of aspiration pneumonia 61 months after symptom onset. Neuropathological examination revealed severe cerebral atrophy with moderate to severe gliosis, but the brainstem was well preserved. Various-sized and non-confluent vacuole type spongiform changes were extensively observed in the cerebral cortices. Prion protein (PrP) immunostaining revealed weak and synaptic-type PrP deposits in the cerebral cortices. We consider that long-term tube feeding, and very mild brainstem involvement may be associated with the long-term survival of our V180I gCJD patient.

Eva Bagyinszky,1 Vo Van Giau,1 Young Chul Youn,2 Seong Soo A An,1 SangYun Kim3 1Department of Bionano Technology, Gachon Bionano Research Institute, Gachon University, Gyeonggi-do, South Korea; 2Department of Neurology, Chung-Ang University College of Medicine, Seoul, South Korea; 3Department of Neurology, Seoul National University College of Medicine & Neurocognitive Behavior Center, Seoul National University Bundang Hospital, Seongnam, South Korea Abstract: Abnormal prion proteins are responsible for several fatal neurodegenerative diseases in humans and in animals, including Creutzfeldt–Jakob disease (CJD), Gerstmann–Sträussler–Scheinker disease, and fatal familial insomnia. Genetics is important in prion diseases, but in the most cases, cause of diseases remained unknown. Several mutations were found to be causative for prion disorders, and the effect of mutations may be heterogeneous. In addition, different prion mutations were suggested to play a possible role in additional phenotypes, such as Alzheimer’s type pathology, spongiform encephalopathy, or frontotemporal dementia. Pathogenic nature of several prion mutations remained unclear, such as M129V and E219K. These two polymorphic sites were suggested as either risk factors for different disorders, such as Alzheimer’s disease (AD), variant CJD, or protease-sensitive prionopathy, and they can also be disease-modifying factors. Pathological overlap may also be possible with AD or progressive dementia, and several patients with prion mutations were initially diagnosed with AD. This review also introduces briefly the diagnosis of prion diseases and the issues with their diagnosis. Since prion diseases have quite heterogeneous phenotypes, a complex analysis, a combination of genetic screening, cerebrospinal fluid biomarker analysis and imaging technologies could improve the early disease diagnosis. Keywords: genetics, mutation, prion, PRNP gene, Creutzfeldt–Jakob disease, Gerstmann–Sträussler–Scheinker disease, fatal familial insomnia, Alzheimer’s disease, diagnosis

Conformational conversion of the cellular isoform of prion protein, PrPC, into the abnormally folded, amyloidogenic isoform, PrPSc, is an underlying pathogenic mechanism in prion diseases. The diseases manifest as sporadic, hereditary, and acquired disorders. Etiological mechanisms driving the conversion of PrPC into PrPSc are unknown in sporadic prion diseases, while prion infection and specific mutations in the PrP gene are known to cause the conversion of PrPC into PrPSc in acquired and hereditary prion diseases, respectively. We recently reported that a neurotropic strain of influenza A virus (IAV) induced the conversion of PrPC into PrPSc as well as formation of infectious prions in mouse neuroblastoma cells after infection, suggesting the causative role of the neuronal infection of IAV in sporadic prion diseases. Here, we discuss the conversion mechanism of PrPC into PrPSc in different types of prion diseases, by presenting our findings of the IAV infection-induced conversion of PrPC into PrPSc and by reviewing the so far reported transgenic animal models of hereditary prion diseases and the reverse genetic studies, which have revealed the structure-function relationship for PrPC to convert into PrPSc after prion infection.

Creutzfeldt–Jakob disease (CJD) belongs to a group of prion disease that is caused by abnormally folded proteins and is clinically characterized by rapidly progressive cognitive decline, gait abnormalities, and myoclonus. Familial CJD is very rare and is described only in few families around the world. We report a case with rapidly progressive cognitive decline, ataxia, and myoclonus, with a history of several members of his family developing similar symptoms and succumbing to it. Clinical presentation and neuroimaging were suggestive of CJD. On genetic analysis, our index case and two of his family members (younger brother and younger son) were found to have D178N mutation in PRNP gene. The polymorphism of the 129th amino acid was V/V. We report the first kindred familial CJD from South-East Asia with genetically proven D178N-129V haplotype.

International audience; Genetic Creutzfeldt-Jakob disease is due to mutations in the PRNP gene. Only two families with a PRNP G114V mutation have been described around the world. We report the first European case, who had no family history and initially presented with isolated deficit in hippocampus-dependent memory. Initial investigations were normal except for elevated total tau protein in the cerebrospinal fluid. He died 4 years after disease onset. This case highlights the diagnostic difficulties posed by genetic Creutzfeldt-Jakob disease, and shows that genetic analyses should be considered even in sporadic cases.

Prion diseases are caused by misfolded prion protein (PrPSc) and are accompanied by spongiform vacuolation of brain lesions. Approximately three centuries have passed since prion diseases were first discovered around the world, however, the exact role of certain factors affecting the causative agent of prion diseases is still debatable. In recent studies, somatic mutations were assumed to be cause of several diseases. Thus, we postulated that genetically unstable cancer tissue may cause somatic mutations in the prion protein gene (PRNP), which could trigger the onset of prion diseases. To identify somatic mutations in the PRNP gene in cancer tissues, we analyzed somatic mutations in the PRNP gene in cancer patients using the Cancer Genome Atlas (TCGA) database. In addition, to evaluate whether the somatic mutations in the PRNP gene in cancer patients had a damaging effect, we performed in silico analysis using PolyPhen-2, PANTHER, PROVEAN, and AMYCO. We identified a total of 48 somatic mutations in the PRNP gene, including 8 somatic mutations that are known pathogenic mutations of prion diseases. We identified significantly different distributions among the types of cancer, the mutation counts, and the ages of diagnosis between the total cancer patient population and cancer patients carrying somatic mutations in the PRNP gene. Strikingly, although invasive breast carcinoma and glioblastoma accounted for a high percentage of the total cancer patient population (9.9% and 5.4%, respectively), somatic mutations in the PRNP gene have not been identified in these two cancer types. We suggested the possibility that somatic mutations of the PRNP gene in glioblastoma can be masked by a diagnosis of prion disease. In addition, we found four aggregation-prone somatic mutations, these being L125F, E146Q, R151C, and K204N. To the best of our knowledge, this is the first specific analysis of the somatic mutations in the PRNP gene in cancer patients.

Abnormal prion proteins are responsible for several fatal neurodegenerative diseases in humans and in animals, including Creutzfeldt–Jakob disease (CJD), Gerstmann–Sträussler–Scheinker disease, and fatal familial insomnia. Genetics is important in prion diseases, but in the most cases, cause of diseases remained unknown. Several mutations were found to be causative for prion disorders, and the effect of mutations may be heterogeneous. In addition, different prion mutations were suggested to play a possible role in additional phenotypes, such as Alzheimer’s type pathology, spongiform encephalopathy, or frontotemporal dementia. Pathogenic nature of several prion mutations remained unclear, such as M129V and E219K. These two polymorphic sites were suggested as either risk factors for different disorders, such as Alzheimer’s disease (AD), variant CJD, or protease-sensitive prionopathy, and they can also be disease-modifying factors. Pathological overlap may also be possible with AD or progressive dementia, and several patients with prion mutations were initially diagnosed with AD. This review also introduces briefly the diagnosis of prion diseases and the issues with their diagnosis. Since prion diseases have quite heterogeneous phenotypes, a complex analysis, a combination of genetic screening, cerebrospinal fluid biomarker analysis and imaging technologies could improve the early disease diagnosis.

As an experimental model of acquired Creutzfeldt-Jakob disease (CJD), we performed transmission studies of sporadic CJD using knock-in mice expressing human prion protein (PrP). In this model, the inoculation of the sporadic CJD strain V2 into animals homozygous for methionine at polymorphic codon 129 (129 M/M) of the PRNP gene produced quite distinctive neuropathological and biochemical features, that is, widespread kuru plaques and intermediate type abnormal PrP (PrPSc). Interestingly, this distinctive combination of molecular and pathological features has been, to date, observed in acquired CJD but not in sporadic CJD. Assuming that these distinctive phenotypic traits are specific for acquired CJD, we revisited the literature and found two cases showing widespread kuru plaques despite the 129 M/M genotype, in a neurosurgeon and in a patient with a medical history of neurosurgery without dura mater grafting. By Western blot analysis of brain homogenates, we revealed the intermediate type of PrPSc in both cases. Furthermore, transmission properties of brain extracts from these two cases were indistinguishable from those of a subgroup of dura mater graft-associated iatrogenic CJD caused by infection with the sporadic CJD strain V2. These data strongly suggest that the two atypical CJD cases, previously thought to represent sporadic CJD, very likely acquired the disease through exposure to prion-contaminated brain tissues. Thus, we propose that the distinctive combination of 129 M/M genotype, kuru plaques, and intermediate type PrPSc, represents a reliable criterion for the identification of acquired CJD cases among presumed sporadic cases.

A b s t r a c t The cellular prion protein (PrPC) is a membrane-bound glycoprotein mainly present in the central nervous system which is necessary for the establishment and further evolution of prion disease in human and animals. The aim of the present study was to investigate the PrPC protein in brain tissues of black Bengal goat. Fifteen brain tissues were collected from different slaughter houses of three districts (Mymensingh, Manikgonj and Netrokona) of Bangladesh during January to February, 2011. The PrPC protein was detected in the brain tissues of black Bengal goats using polymerase chain reaction. The result showed all positive (100%) of the amplified samples. The standardized PCR could be used for detection of PrPC protein in different tissues of animals and humans. Sequencing of PrP gene in the black Bengal goats for the risk assessment of scrapie is needed for further study. To our knowledge, detection of PrPC protein in the brain tissues of indigenous goats is the first time in Bangladesh.

Genetic Creutzfeldt-Jakob disease (CJD) is associated with mutations in the human PrP gene (PRNP) on chromosome 20p12-pter. Pathogenic mutations have been identified in 10-15% of all CJD patients, who often have a family history of autosomal-dominant pattern of inheritance and variable penetrance. However, the use of genetic tests implemented by surveillance networks all over the world increasingly identifies unexpectedly PRNP mutations in persons apparently presenting with a sporadic form of CJD. A high phenotypic variability was reported in genetic prion diseases, which partly overlap with the features of sporadic CJD. Here we review recent advances on the epidemiologic, clinical, and neuropathologic features of cases that phenotypically resemble CJD linked to point and insert mutations of the PRNP gene. Multidisciplinary studies are still required to understand the phenotypic spectrum, penetrance, and significance of PRNP mutations.

Scrapie was the first prion disease to be recognised and the study of this disease in sheep and goats has provided a wealth of information not only for scrapie but also for the other prion diseases. All prion diseases are under strong genetic control of the prion gene PRNP, independent of whether they are typical or atypical scrapie and which of the different prion strains is causing infection. Decades of studies using experimental disease challenges and field surveys have established disease association models, in which species-specific amino acid variations in the prion or PrP protein, encoded by the PRNP gene, can predict disease susceptibility or resistance. PRNP genetics represents an important and successful basis for implementing scrapie eradication strategies in sheep and goats. In general terms these studies have revealed that there appear to be many more amino acid changes in PrP leading to increased resistance than to higher susceptibility. Most changes are in the globular part of PrP protein and three regions appear to have major influence. This knowledge can be transferred into prion diseases of other species to facilitate genetic control strategies. However, an obstacle remains with the lack of fully understanding the underlying molecular mechanism, impeding our ability to deal with the difference in the genetic control between typical and atypical forms of scrapie or to predict association in newly infected species. This chapter will discuss the advances in both typical and atypical scrapie from a genetic perspective.

Prion diseases are fatal neurodegenerative diseases that affect humans and non-human mammals. Different alleles of the prion protein gene (PRNP) of humans and sheep are associated with varying susceptibilities to transmissible spongiform encephalopathies. Chronic wasting disease (CWD) is a prion disease of cervids, and polymorphisms at specific codons in the PRNP gene are associated with this disease. To assess the susceptibility of free-ranging deer to CWD, polymorphisms in PRNP were examined in the Korean water deer (Hydropotes inermis argyropus), focusing on codons that are potentially associated with CWD susceptibility (95, 96, 116, 132, 225, and 226). CWD surveillance was conducted by an antigen ELISA of tissue samples from 545 Korean water deer collected in eight provinces of the Republic of Korea. No prion protein associated with CWD was detected in any of the samples. These results suggest that PRNP of the Korean water deer shows low variation and the species has not been infected with CWD.

The misfolding of the cellular prion protein (PrPC) causes fatal neurodegenerative diseases. Yet PrPC is highly conserved in mammals, suggesting that it exerts beneficial functions preventing its evolutionary elimination. Ablation of PrPC in mice results in well-defined structural and functional alterations in the peripheral nervous system. Many additional phenotypes were ascribed to the lack of PrPC, but some of these were found to arise from genetic artifacts of the underlying mouse models. Here, we revisit the proposed physiological roles of PrPC in the central and peripheral nervous systems and highlight the need for their critical reassessment using new, rigorously controlled animal models.

The article presents the results of the research on methods of identification and quantitative determination of prion proteins in biological samples and multicomponent mixtures based on them. Analysis of nucleotide sequence of DNA encoding the PRNP gene of the prion protein, including phylogenetic and comparative analysis of nucleotide sequences of normal and pathogenic prion protein in cattle, was performed. Oligonucleotide primers for amplification of the PRNP gene of pathogenic prion protein were designed and synthesized. The high specificity of the developed test system was confirmed.

Prion diseases, or transmissible spongiform encephalopathies, are neurodegenerative diseases, which affect human and many species of animals with 100% fatality rate. The most accepted etiology for prion disease is 'prion', which arises from the conversion from cellular PrP(C) to the pathological PrP(Sc). This review discussed the characteristic structure of PrP, including PRNP gene, PrP(C), PrP(Sc), PrP amyloid, and prion strains.

Prion diseases are a group of infectious fatal neurodegenerative diseases. The conformational conversion of a cellular prion protein (PrP(C)) into an abnormal misfolded isoform (PrP(Sc)) is the key event in prion diseases pathology. Under normal conditions, the high-energy barrier separates PrP(C) from PrP(Sc) isoform. However, pathogenic mutations, modifications as well as some cofactors, such as glycosaminoglycans, nucleic acids, and lipids, could modulate the conformational conversion process. Understanding the mechanism of conformational conversion of prion protein is essential for the biomedical research and the treatment of prion diseases. Particularly, the characterization of cofactors interacting with prion protein might provide new diagnostic and therapeutic strategies.

Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare but fatal type of spongiform encephalopathy with unidentified origin. The conjoining methionine-valine polymorphism of PRNP gene at codon 129 and two types of prion protein (PrPsc types 1 and 2) described the six different molecular subtypes (MM1, MM2, MV1, MV2, VV1 and VV2) of sCJD. Presumptive subtype specific diagnosis showed differential clinical manifestations and levels of CSF 14-3-3 protein. Even with the above mentioned differential diagnostic guidelines, pre-mortem subtype specific diagnosis of sCJD can be unreliable with high rates of misdiagnosis. The need for more reliable biomarkers for improving the diagnosis as well as understanding the pathogenesis of this mysterious ailment is amplified. This review compiles the levels of CSF proteins, i.e., PrPC, PrPSC 14-3-3, tau, phosphorylated tau, S100B, neuron-specific enolase (NSE) alpha-synuclein and beta-amyloid to differential diagnosis subtype specific sCJD cases. The detection of pre-mortem distinction targets might be useful diagnostic tool for sCJD in subtype specific manner and might lead towards differential treatment approaches.

• Fatal familial insomnia is a rare neurodegenerative hereditary autosomal dominant prion disease.

This issue contains a number of articles on neurodegenerative diseases, most of them genotypically analyzed with next-generation sequencing. Readers will find articles identifying potential mutations in new genes, articles examining different phenotypes associated with variation in the same gene, and a report showing an unusual phenotype associated with a known mutation in the PRNP gene. Finally, the imaging phenotypes of mutations in 2 different frontotemporal lobar dysfunction (FTLD) genes are compared.

Msalya, G., Shimogiri, T., Okamoto, S., Kawabe, K. and Maeda, Y. 2012. Short Communication: The double deletion diplotype showed low levels of prion protein at two indel loci of PRNP in the medulla oblongata of Japanese Brown cattle. Can. J. Anim. Sci. 92: 153–157. Transmissible spongiform encephalopathies (TSEs) are a class of fatal neurodegenerative diseases caused by abnormally folded prion proteins (PrP). The PrP is necessary for the transmission and propagation of TSE diseases. In this study, PrP was quantified in the medulla oblongata of 39 Japanese Brown (JBr) animals that were genotyped for two indels in the PRNP gene – a 23 bp deletion in the promoter region and a 12 bp deletion in the first intron. The mean level of PrP was greater in the ++/++ diplotype than in −−/−− and +−/+− diplotypes, although the differences were not significant. These results suggest that the amount of PrP in the medulla oblongata of animals is related to these indels. However, given that there have been no reported cases of BSE in Japanese Brown animals, the relationship of the indels and PrP levels with the incidence of BSE is unclear.

Prion diseases are fatal transmissible neurodegenerative diseases of humans and various vertebrate species. In their natural hosts these conditions are characterised by prolonged incubation times prior to the onset of clinical signs of terminal disease. Accordingly, tractable models of mammalian prion disease are required in order to better understand the mechanisms of prion replication and prion-induced neurotoxicity. Transmission of prion diseases can occur across a species barrier and this is facilitated in recipients transgenic for the same PrP gene as the individual from which the infectious prions are derived. Here we have tested the hypothesis that exogenous ovine prions can induce neurotoxicity in Drosophila melanogaster transgenic for ovine PrP. Drosophila that expressed ovine PrP pan neuronally and inoculated with ovine prions at the larval stage by oral exposure to scrapie-infected sheep brain homogenate showed markedly accelerated locomotor and survival defects. ARQ PrP transgenic Drosophila exposed to scrapie-infected brain homogenate showed a significant and progressive reduction in locomotor activity compared to similar flies exposed to normal sheep brain homogenate. The prion-induced locomotor defect was accompanied by the accumulation of potentially misfolded PrP in the brains of prion-inoculated flies. VRQ PrP transgenic Drosophila, which expressed less ovine PrP than ARQ flies, showed a reduced median survival compared to similar flies exposed to normal sheep brain homogenate. These prion-induced phenotypic effects were PrP-mediated since ovine prions were not toxic in non-PrP transgenic control flies. Our observations provide the basis of an invertebrate model of transmissible mammalian prion disease.

The suggested role of cellular prion protein (PrP (C) ) in mediating the toxic effects of oligomeric amyloid β peptide (Aβ) in Alzheimer disease (AD) is controversial. To address the hypothesis that variable PrP (C) expression is involved in AD pathogenesis, we analyzed PrPC expression in the frontal and temporal cortices and hippocampus of individuals with no cognitive impairment (NCI), amnestic mild cognitive impairment (aMCI), mild AD (mAD), and AD. We found that PrP (C) expression in all brain regions was not significantly altered among the various patient groups. In addition, PrP (C) levels in all groups did not correlate with expression of methionine (M) or valine (V) at codon 129 of the PrP gene, a polymorphism that has been linked in some studies to increased risk for AD, and which occurs in close proximity to the proposed binding region for the oligomeric Aβ peptide. Our results indicate that, if PrP (C) is involved in mediating the toxic effects of the oligomeric Aβ peptide, these effects occur independently of steady state levels of PrP or the codon 129 polymorphism.

Transmissible spongiform encephalopathies (TSEs) or prion diseases are unique disorders that are not caused by infectious micro-organisms (bacteria or fungi), viruses or parasites, but rather seem to be the result of an infectious protein. TSEs are comprised of fatal neurodegenerative disorders affecting both human and animals. Prion diseases cause sponge-like degeneration of neuronal tissue and include (among others) Creutzfeldt-Jacob disease in humans, bovine spongiform encephalopathy (BSE) in cattle and scrapie in sheep. TSEs are characterized by the formation and accumulation of transmissible (infectious) disease-associated protease-resistant prion protein (PrP(Sc)), mainly in tissues of the central nervous system. The exact molecular processes behind the conversion of PrP(C) into PrP(Sc) are not clearly understood. Correlations between prion protein polymorphisms and disease have been found, however in what way these polymorphisms influence the conversion processes remains an enigma; is stabilization or destabilization of the prion protein the basis for a higher conversion propensity? Apart from the disease-associated polymorphisms of the prion protein, the molecular processes underlying conversion are not understood. There are some notions as to which regions of the prion protein are involved in refolding of PrP(C) into PrP(Sc) and where the most drastic structural changes take place. Direct interactions between PrP(C) molecules and/or PrP(Sc) are likely at the basis of conversion, however which specific amino acid domains are involved and to what extent these domains contribute to conversion resistance/sensitivity of the prion protein or the species barrier is still unknown.

The clinical features of 44 Finnish patients with Creutzfeldt-Jakob disease (CJD) were analyzed with special emphasis on the differences between the sporadic and familial forms. The 32 sporadic patients comprised all neuropathologically verified cases of CJD in 1974-89 in Finland. The 12 familial patients were members of the same pedigree where CJD has been linked with a mutation at codon 178 of the PRNP gene. The median age at the onset of the disease was 62.5 years and median duration 4.5 months in sporadic patients, and 49 years and 20.5 months in familial CJD, respectively. 90 percent of both sporadic and familial patients had myoclonus. Typical periodic EEG change was seen in 72% of sporadic patients, whereas the familial patients showed only a progressive slowing of EEG.

A young man, presenting with early onset of personality and behavioural changes followed by slowly progressive cognitive impairment associated with marked bi-parietal cerebral atrophy, was found to carry a novel seven extra-repeat insertional mutation in the prion protein gene (PRNP). In vitro, the mutated recombinant prion protein (PrP) showed biochemical properties that were consistent with pathological PrP variants. Our results further underline the heterogeneity of neurological pictures associated with insertional mutations of PRNP, indicating the diagnostic difficulties of sporadic cases with early-onset atypical dementia.

Codon 129 polymorphism of the prion protein gene represents a major genetic risk factor for Creutzfeldt-Jakob disease (CJD). Both CJD and Alzheimer's disease (AD) are brain amyloidoses and it would be possible that codon 129 polymorphism plays a role in the susceptibility to AD. In order to investigate this polymorphism in AD the distribution of polymorphic codon 129 of the PRNP gene in 194 probable AD and 124 controls selected in Italy and 109 neuropathologically verified AD and 58 matched controls recruited in the USA was studied. No significant association was found for the PRNP polymorphism in AD compared to controls either in Probable or in Definite AD series even after stratification for APOE polymorphism. This study does not support a role of PRNP polymorphism as a susceptibility factor for AD.

We report a 79-year-old Japanese man with histlogically-diagnosed Creutzfeldt-Jakob disease (CJD) with codon 129 polymorphism and codon 180 point mutation. At the time of the first examination, we diagnosed and treated as Alzheimer's disease with cerebrovascular disease because of laterality of cortex accumulation and an accumulation decrease of perforating branch areas at the SPECT ((123)I-IMP). His status rapidly progressed to an apallic state and died of lung abscess 12 months later. None of the members of his family had neuromuscular disorders. EEG (electroencephalogram) did not reveal periodic synchronous discharges (PSD). Prion protein gene analysis showed Codon 129 polymorphism (Met/Val) and codon 180 point mutation (Val/Ile). The autopsy findings revealed spongiform changes and numerous senile plaque formation in the cerebral cortex. The hippocampus and the cerebellar cortex were well preserved and did not show lacunar infarctions. CJD patients with combination of the codon 180 point mutation and codon 129 polymorphism of the PrP gene have rarely been reported.

Polymorphisms of the prion protein gene are associated with differing susceptibilities to transmissible spongiform encephalopathy diseases, as shown for variant Creutzfeldt–Jakob disease in humans and scrapie in sheep, but not yet in cattle. Imposition of control measures in the UK, including a reinforced ruminant feed ban in 1996, has led to a reduction in the incidence of bovine spongiform encephalopathy (BSE). BSE-affected cattle born after 1996 in Great Britain have been termed born-after-the-reinforced-ban (BARB) cases. In this study, the PrP gene coding region from 100 BARB BSE cases and 66 matched healthy-control cattle was sequenced to investigate whether this would reveal a genetic basis to their origin. Polymorphisms identified were not found to be associated with increased susceptibility to BSE in the BARB cases. Analysis of BARB cases grouped either by clinical status or by whether they formed an isolated or clustered case was also undertaken, but differences were not found to be significant.

More than 100,000 genetic variants are reported to cause Mendelian disease in humans, but the penetrance-the probability that a carrier of the purported disease-causing genotype will indeed develop the disease-is generally unknown. We assess the impact of variants in the prion protein gene (PRNP) on the risk of prion disease by analyzing 16,025 prion disease cases, 60,706 population control exomes, and 531,575 individuals genotyped by 23andMe Inc. We show that missense variants in PRNP previously reported to be pathogenic are at least 30 times more common in the population than expected on the basis of genetic prion disease prevalence. Although some of this excess can be attributed to benign variants falsely assigned as pathogenic, other variants have genuine effects on disease susceptibility but confer lifetime risks ranging from < 0.1 to similar to 100%. We also show that truncating variants in PRNP have position-dependent effects, with true loss-of-function alleles found in healthy older individuals, a finding that supports the safety of therapeutic suppression of prion protein expression.

Polymorphic microsatellite sites within 148 kb of the human prion gene complex, including the genes PRNP, PRND and PRNT, were analysed together with the Codon129 variants regarding 50 CJD (Creutzfeldt-Jakob Disease) patients and 46 non-diseased control persons. Three of the sites (MM03, MM04, Codon129) differed significantly (P0.05) for their allele frequencies between the two groups--the predominant allele being always more frequent in the CJD group. Deviations from Hardy-Weinberg Equilibrium were mainly obtained in the CJD group--in all cases with a reduction of the observed heterozygosity. The sites MM03, MM04 and Codon129 were also analysed for their haplotypes. The predominant homozygous haplotype combination was more frequently observed in the CJD group (0.875) than in the non-diseased group (0.38). Thus the different polymorphic sites indicate that high CJD disposition is associated with homozygosity in the PRNP gene.

One of the arguments in favor of the protein-only hypothesis of transmissible spongiform encephalopathies is the link between inherited prion diseases and specific mutations in the PRNP gene. One such mutation (Asp178 → Asn) is associated with two distinct disorders: fatal familial insomnia or familial Creutzfeldt−Jakob disease, depending upon the presence of Met or Val at position 129, respectively. In this study, we have characterized the biophysical properties of recombinant human prion proteins (huPrP90−231) corresponding to the polymorphic variants D178N/M129 and D178N/V129. In comparison to the wild-type protein, both polymorphic forms of D178N huPrP show a greatly increased propensity for a conversion to β-sheet-rich oligomers (at acidic pH) and thioflavine T-positive amyloid fibrils (at neutral pH). Importantly, the conversion propensity for the D178N variant is strongly dependent upon the M/V polymorphism at position 129, whereas under identical experimental conditions, no such dependence is obs...

Summary Transmissible spongiform encephalopathy (TSE) is a neurodegenerative disorder in humans and animals. Polymorphisms and mutations in the prion protein (PRNP) gene have been associated with the incidence of natural and experimental TSE and the incubation period length. In this study, we determined PRNP polymorphisms in Chinese ovine, caprine and bovine breeds using 400 samples from 13 ovine and caprine breeds and 250 samples from nine bovine breeds. In the ovine and caprine PRNP gene, we found five previously unreported amino acid polymorphisms and two silent nucleotide alterations. In bovine PRNP, we found eight previously unreported amino acid polymorphisms and six silent nucleotide alterations.

TRANSMISSIBLE spongiform encephalopathies (TSEs) are a group of neurodegenerative diseases caused by the accumulation in the central nervous system (CNS) of an anomalous isoform called prion protein (Prusiner 1982). Bovine spongiform encephalopathy (BSE) represents one of the most important food crises of past decades in Europe. BSE started in the UK, due to cattle consumption of feedstuff contaminated with prions (Wilesmith and others 1992). In Europe, efforts have focused on eradicating the disease in the bovine population. However, since sheep and goats are susceptible to prion diseases, eradication efforts in these species have to be considered; in fact, in 2005 the first case of natural BSE in a goat from France was diagnosed (Eloit and others 2005). These findings imply that BSE in small ruminants (particularly goats) could represent a danger for human health and therefore various strategies must be considered to avoid infection. It has been recognised that polymorphisms of the PRNP gene are responsible for some element of susceptibility or resistance to prion diseases. Studies in sheep have shown that the haplotype …

Prion diseases are unique in that they comprise sporadic, genetic, and iatrogenically or environmentally acquired forms. When disease is acquired by peripheral route, neuroinvasion occurs via at least two different neural pathways (vague and splanchnic nerves) and is usually preceded by prion propagation in secondary lymphoid organs. Conversely, in the other etiologic forms, PrPSc formation occurs within, and is apparently limited to, the CNS. Longitudinal studies on experimental scrapie indicate that substantial neuropathologic changes (i.e., glial activation and nerve cell degeneration) already are present before the onset of symptoms and are topographically related to PrPSc deposits. Accordingly, any effective intervention should start during the preclinical stage of disease, and be aimed at preventing neuroinvasion or PrPSc propagation in the CNS. Unfortunately, no tests are available currently to detect presymptomatic individuals, except for carriers of pathogenic mutations of the PRNP gene. Inhibition of PrPSc formation can be achieved through (1) abrogation of PrPC synthesis or prevention of its transport to the cell surface; (2) stabilization of the PrPC structure to make its conformational change unfavorable; (3) sequestration of PrPSc; (4) reversion of PrPSc to a protease-sensitive form; or (5) interference with the interaction between PrPC, PrPSc, and other macromolecules that feature in the conversion process. The compounds that have some effectiveness in in vitro, cell culture, or animal models of prion disease seem to operate through one of these mechanisms (see Table 1); however, even the most effective drugs only work when administered at the time of infection or very short thereafter, and these conditions are incurable at present. The heterogeneity and complexity of the etiopathogenesis of prion diseases suggest that various strategies and a combination of several compounds with different modes of actions are likely necessary for prevention and treatment. Major efforts should be focused on the development of preclinical diagnostic tests in conjunction with immunization strategies for diseases acquired by peripheral route and identification of more effective compounds for the other etiological forms.

To assess the risk of the de novo emergence of the agent of transmissible spongiform encephalopathies in cultured cells, we examined the stability of the prion protein-encoding (PRNP) gene in HeLa cells and in cultures contaminated with HeLa cells that have been passaged extensively for over 50 years. Various sub-lineages of HeLa cells showed that some contained a mixture of a truncated PRNP gene (R3-R4 deletion) and a full-length PRNP gene, while others were homozygous for the R3-R4 deletion. That finding suggests that the progenitor of several popular sub-lineages of HeLa must have lost part or all of chromosome 20 early in the history of HeLa cells. No mutations were found in the PRNP genes. We conclude that the spontaneous appearance of mutations leading to expression of abnormal prion proteins in continuously passaged heteroploid cell lines is unlikely to pose a substantial risk for the safe production of biologicals in such cells.

Elucidation of prion protein (PrP) functions is crucial to fully understand prion diseases. A major approach to studying PrP functions is the use of PrP gene-knockout (Prnp (-/-)) mice. So far, six types of Prnp (-/-) mice have been generated, demonstrating the promiscuous functions of PrP. Recently, other PrP family members, such as Doppel and Shadoo, have been found. However, information obtained from comparative studies of structural and functional analyses of these PrP family proteins do not fully reveal PrP functions. Recently, varieties of Prnp (-/-) cell lines established from Prnp (-/-) mice have contributed to the analysis of PrP functions. In this mini-review, we focus on Prnp (-/-) cell lines and summarize currently available Prnp (-/-) cell lines and their characterizations. In addition, we introduce the recent advances in the methodology of cell line generation with knockout or knockdown of the PrP gene. We also discuss how these cell lines have provided valuable insights into PrP functions and show future perspectives.

BJECTIVE: To report two members of the same family carrying the valine to isoleucine point mutation of the prion protein gene (PRNP) and presenting with visual symptoms as initial manifestation as in the "Heidenhain variant" of sporadic Creutzfeldt-Jakob disease (CJD). METHODS: Patients underwent neurological examination, electroencephalogram (EEG), brain magnetic resonance images (MRI) and cerebrospinal fluid (CSF) analysis including the Real Time Quaking Induced Conversion (RT-QuIC) test. Disease-specific mutations and polymorphism at codon 129 of the PRNP gene were also studied. RESULTS: Isolated visual symptoms characterized disease onset of both patients followed by progressive neurological signs, dementia and death in 3 (proband) and 9 (his aunt) months. RT-QuIC analysis of CSF samples of both patients revealed the presence of the pathological prion protein and DNA analysis the V210I point mutation of the PRNP and methionine homozygosity at the polymorphic codon 129. CONCLUSIONS: This report suggests to consider the diagnosis of V210I genetic CJD in patients presenting with the Heidenhain form of CJD and highlights the importance of genetic testing in all patients with isolated visual manifestations at onset followed by progressive neurological signs and dementia.

The transmissible spongiform encephalopathy diseases are transmissible, neurodegenerative, and inevitably fatal diseases of the central nervous system. There are no sensitive diagnostic tests to detect infection early during disease and no effective treatments are available. Accumulation of an abnormally aggregated and protease resistant form of the mammalian prion protein (PrP) is a key facet of TSE pathogenesis and an obvious target for early diagnosis and therapeutic intervention. Synthetic peptides to certain regions of the PrP gene have been shown to inhibit formation of the abnormal disease-associated PrP isoform. Peptides based on the PrP sequence may be useful as anti-TSE therapeutics. Specific interactions between PrP peptides and the abnormal PrP protein could also form the basis of a specific and sensitive diagnostic test.

The normal cellular prion protein, PrP(C) is a highly conserved and widely expressed cell surface glycoprotein in all mammals. The expression of PrP is pivotal in the pathogenesis of prion diseases; however, the normal physiological functions of PrP(C) remain incompletely understood. Based on the studies in cell models, a plethora of functions have been attributed to PrP(C). In this paper, we reviewed the potential roles that PrP(C) plays in cell physiology and focused on its contribution to tumorigenesis.

The polymorphism at codon 129 of the prion protein gene (PRNP) is a major risk factor for Creutzfeldt–Jakob disease (CJD). Several authors reported neuropathological and clinical overlapping between CJD and Alzheimer’s disease (AD), with a few association studies generating conflicting results. To investigate the distribution of this polymorphism in AD, we selected 58 patients with probable AD and 73 controls from a Brazilian population. There was no association between the PRNP polymorphism at codon 129 and AD. Our meta-analysis (performed using Alzgene; http://www.alzgene.org) along with previous studies conducted in Brazil demonstrated a negative association.