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There has been no report on Chronic wasting disease (CWD) cases in Japan to date; however, there is concern about the geographic spread of CWD. To clarify the CWD status in Japan, we conducted CWD monitoring using real-time quaking-induced conversion (RT-QuIC) assay which can detect the low level of CWD prions. A total of 690 obex samples collected from sika deer and Reeves's muntjac in Hokkaido and Honshu was tested for CWD prions. No CWD-positive cases were found, suggesting that CWD is nonexistent in Japan. Our results also indicate that RT-QuIC assay is useful for continuous monitoring of CWD. Furthermore, nucleotide sequence analysis of the PrP gene revealed sika deer in Japan harbor CWD susceptible allele.

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.

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...

We report a detailed study of a cohort of sporadic Creutzfeldt-Jakob disease (sCJD) VV1–2 type-mixed cases (valine homozygosity at codon 129 of the prion protein, PrP, gene harboring disease-related PrP, PrPD, types 1 and 2). Overall, sCJDVV1–2 subjects showed mixed clinical and histopathological features, which often correlated with the relative amounts of the corresponding PrPD type. However, type-specific phenotypic characteristics were only detected when the amount of the corresponding PrPD type exceeded 20–25%. Overall, original features of types 1 (T1) and 2 (T2) in sCJDVV1 and -VV2, including rostrocaudal relative distribution and conformational indicators, were maintained in sCJDVV1–2 except for one of the two components of T1 identified by electrophoretic mobility as T121. The T121 conformational characteristics shifted in the presence of T2, inferring a conformational effect of PrPD T2 on T121. The prevalence of sCJDVV1–2 was 23% or 57% of all sCJDVV cases, depending on whether standard or highly sensitive type-detecting procedures were adopted. This study, together with previous data from sCJDMM1–2 (methionine homozygosity at PrP gene codon 129) establishes the type-mixed sCJD variants as an important component of sCJD, which cannot be identified with current non-tissue based diagnostic tests of prion disease.

Scrapie is a lethal neurodegenerative disease of sheep and goats caused by the misfolding of the prion protein. Variants such as M142, D145, S146, H154, Q211, and K222 were experimentally found to increase resistance or extend scrapie incubation period in goats. We aimed to identify polymorphisms in the Afar and Arsi-Bale goat breeds of Ethiopia and computationally assess the effect of variants on prion protein stability. In the present study, four non-synonymous novel polymorphisms G67S, W68R, G69D, and R159H in the first octapeptide repeat and the highly conserved C-terminus globular domain of goat PrP were detected. The resistant genotype, S146, was detected in >50% of the present population. The current study population showed a genetic diversity in Ethiopian goat breeds. In the insilico analysis, the R68 variant was predicted to increase stability while S67, D69, and H159 decrease the stability of prion protein. The new variants in the octapeptide repeat motif were predicted to decrease amyloidogenicity but H159 increased the hotspot sequence amyloidogenic propensity. These novel variants could be the source of conformational flexibility that may trigger the gain or loss of function by prion protein. Further experimental study is required to depict the actual effects of variants on prion protein stability.

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.

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.

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.

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.

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 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.

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.

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 PCR-amplified prion protein (PrP) gene was sequenced to determine the frequency of scrapie-associated as well as novel PrP genotypes in 72 healthy goats representing five breeds. A total of six genotypes were detected, resulting from the three reported 143 (H/R), 154 (R/H) and 240 (S/P) and the two novel 39 (S/R) and 185 (I/F) amino acid polymorphisms. Of the four silent mutations 42 (a→g), 138 (c→t), 231 (c→a) and 237 (g→c) detected in this study, 237 (g→c) is novel. A genotype (SIP/RFP) harboring three amino acid polymorphisms 39 (S/R), 185 (I/F) and 240 (S/P) was found in few goats. Although both scrapie-associated genotypes with 143 (H/R) and 154 (R/H) polymorphisms and others with 39 (S/R), 185 (I/F) and 240 (S/P) polymorphisms were present in the studied Pakistani goats, their frequency was lower than that of the wild-type genotype SHRIS/SHRIS (34.7%). These results emphasize the need for further sequencing of the PrP gene in a large number of goats representing the five studied breeds, so that overall PrP variability can be assessed in these breeds in research addressing future concerns about scrapie.

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.

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.

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.

We screened for Japanese Black and Holstein bull sire samples to detect single nucleotide polymorphisms (SNPs) involving animo-acid substitutions in the bovine prion gene in the entire coding region of the PRNP gene. Although three silent SNPs were found, we could not detect any SNP with animo-acid substitution. We also examined the polymorphism of the octapeptide repeat number in these samples. There was no homozygous bull with repeat number 5. The frequency of heterozygous (6/5) bulls was 8% in the Japanese Black bull and 4% in the Holstein bull, respectively. The bull samples used in this study contain popular elite sires, so it appears that the polymorphisms of prion protein (PrP) are rather difficult to find in these two breeds in Japan, except for polymorphism of the octapeptide repeat number.

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.

Two new PCR-based methods were developed to decode prion protein (PrP) gene polymorphisms at codons 136, 154 and 171: a PCR-restriction fragment length polymorphism (RFLP) analysis consisting of two PCR reactions followed by three enzymatic digestions, and a real-time PCR consisting of four reactions with seven fluorogenic probes. Both methods were used to study the distribution of PrP gene polymorphisms in a representative sample (1297 animals) of the populations of the two native breeds of sheep of the Spanish Basque Country, Latxa and Carranzana. Fourteen genotypes were found in the Latxa breed, in which ARQ/ARQ was the genotype most frequently observed (49.3 per cent), followed by ARR/ARQ (32.6 per cent) and ARQ/ARH (5.8 per cent). The genotype associated with the highest resistance to scrapie (ARR/ARR) was present in 5 per cent of the animals analysed. Similar results were observed in the Carranzana sheep.

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 …

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.

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.

Based on its developmental pattern of expression, early studies suggested the implication of the mammalian Prion protein PrP, a glycosylphosphatidylinositol-anchored ubiquitously expressed and evolutionary conserved glycoprotein encoded by the [i]Prnp[/i] gene, in early embryogenesis. However, gene invalidation in several species did not result in obvious developmental abnormalities and it was only recently that it was associated in mice with intra-uterine growth retardation and placental dysfunction. A proposed explanation for this lack of easily detectable developmental-related phenotype is the existence in the genome of one or more gene (s) able to compensate for the absence of PrP. Indeed, two other members of the [i]Prnp[/i] gene family have been recently described, Doppel and Shadoo, and the consequences of their invalidation alongside that of PrP tested in mice. No embryonic defect was observed in mice depleted for Doppel and PrP. Interestingly, the co-invalidation of PrP and Shadoo in two independent studies led to apparently conflicting observations, with no apparent consequences in one report and the observation of a developmental defect of the ectoplacental cone that leads to early embryonic lethality in the other. This short review aims at summarizing these recent, apparently conflicting data highlighting the related biological questions and associated implications in terms of animal and human health.

In the past decade, manipulation of PrP genes by transgenesis in mice has provided important insights into mechanisms of prion propagation and the molecular basis of prion strains and species barriers. Despite these advances, our understanding of these unique pathogens is far from complete. This review focuses on PrP gene knockout and gene replacement studies, PrP structure and function, and transgenic models of human and animal prion diseases. Transgenic approaches will doubtless remain the cornerstone of investigations into the prion diseases in the coming years, which will include mechanistic studies of prion pathogenesis and prion transmission barriers. Transgenic models will also be important tools for the evaluation of potential therapeutic agents for prion diseases.

1. Prion protein (PrPC) is a host-encoded glycoprotein constitutively expressed on the neuronal cell surface. Accumulation of its protease-resistant isoform is closely related to pathologic changes and prion propagation in the brain tissue of a series of prion diseases. However, the physiological role of PrPC remains to be elucidated. 2. After long-term observation, we noted impaired motor coordination and loss of cerebellar Purkinje cells in the aged mice homozygous for a disrupted PrP gene, a finding which strongly suggests that PrPC plays a role in the long-term survival of Purkinje cells. 3. We also describe the resistance of the PrP null mice to the prion, indicating the requirement of PrPC for both the development of prion diseases and the prion propagation.

An abnormal isoform of the prion protein (PrP) appears to be the agent responsible for transmissible spongiform encephalopathies (TSE). The normal isoform of PrP is host-encoded and expressed in the central nervous system. The recent bovine spongiform encephalopathy (BSE) epidemic in the UK and the incidence of prion-related diseases in other animals could indicate that ruminants are highly susceptible to infection via ingestion of prion-contaminated food. Sequence analysis of PrP gene open reading frames from red deer and camel was carried out to investigate sequence variability of these genes among ruminants.

1. The cellular prion protein, designated PrPc, is a key molecule in the prion diseases but its physiological function remains unknown. To elucidate whether PrPc plays some role in the central nervous system, we established a line of mice in which the PrP gene had been disrupted and subsequently conducted long-term observations. 2. Performance in latent learning and passive avoidance was evaluated using water-finding and step-through tests, respectively. 3. PrP –/– mice showed impaired performance in the water-finding test, indicating a disturbance in latent learning, at 23 weeks of age. In the step-through test, although the PrP –/– mice showed normal learning ability and short-term memory retention, they evidenced a significant disturbance in long-term memory retention. 4. These results indicate that PrPc is needed for certain types of learning and memory and that the loss of function of this protein may contribute to the pathogenesis of prion diseases.

Cellular prion-protein is expressed in axons and Schwann cells of peripheral nerves. Some patients with prion diseases show peripheral nerve involvement and prion-protein deficient mice develop age dependent demyelination of peripheral nerves. Therefore we tested the hypothesis that mutations in the prion-protein gene might also cause hereditary motor and sensory neuropathies. We screened 108 patients with a diagnosis of hereditary motor and sensory neuropathies in whom the common genetic defects causing hereditary motor and sensory neuropathies had previously been excluded for mutations in the protein-coding region of the PRNP gene. Mutations in the coding region of the prion-protein gene were not found. We conclude that mutations in the protein coding region of the prion-protein gene are not a common cause of HMSN (95% CI 0–0.034).

Prion diseases caused by the conversion from a soluble normal cellular prion protein into insoluble abnormally folded infectious prions, are invariably fatal and highly infectious degenerative diseases that affect a wide variety of mammalian species. The palindrome and the Glycine-rich conserved segment in the hydrophobic region 109-136 control the conversion from normal prion protein to form into diseased prions. This paper gives detailed reviews on the 109-136 region and presents the studies of its 3D structures and structural dynamics., Comment: This paper was accepted on 18-02-2013 by the journal Acta Biochimica et Biophysica Sinica, in press in Vol 45 No 4, Apr 2013