Prion Disease Phenotype Research Articles

Genetic aspects of human prion diseases.

Human prion diseases are rapidly progressive and fatal neurodegenerative conditions caused by a disease-causing isoform of the native prion protein. The prion protein gene (PRNP) encodes for the cellular prion protein, which is the biological substrate for prion disease transmission and neurotoxicity. Human prion diseases have three etiologies: sporadic, genetic, and acquired. PRNP polymorphisms and pathogenic variants play a large role in the frequency, age at onset, and clinicopathologic phenotype of prion diseases. Genetic prion diseases will be covered in detail and information necessary for clinical care, predictive genetic testing, and genetic counseling will be reviewed. Because the prion protein is necessary for transmission and neurotoxicity, many experimental treatments targeting its production are being investigated and hold potential promise as a disease modifying treatment for all forms of prion disease, including asymptomatic mutation carriers. This article will review genetic aspects of human prion disease and their influence on epidemiology, clinicopathologic phenotype, diagnostics, clinical management, and potential treatment approaches.

Cell biology of prion strains in vivo and in vitro.

The properties of infectious prions and the pathology of the diseases they cause are dependent upon the unique conformation of each prion strain. How the pathology of prion disease correlates with different strains and genetic backgrounds has been investigated via in vivo assays, but how interactions between specific prion strains and cell types contribute to the pathology of prion disease has been dissected more effectively using in vitro cell lines. Observations made through in vivo and in vitro assays have informed each other with regard to not only how genetic variation influences prion properties, but also how infectious prions are taken up by cells, modified by cellular processes and propagated, and the cellular components they rely on for persistent infection. These studies suggest that persistent cellular infection results from a balance between prion propagation and degradation. This balance may be shifted depending upon how different cell lines process infectious prions, potentially altering prion stability, and how fast they can be transported to the lysosome. Thus, in vitro studies have given us a deeper understanding of the interactions between different prions and cell types and how they may influence prion disease phenotypes in vivo.

Aggregation Condition-Structure Relationship of Mouse Prion Protein Fibrils.

Prion diseases are associated with conformational conversion of cellular prion protein into a misfolded pathogenic form, which resembles many properties of amyloid fibrils. The same prion protein sequence can misfold into different conformations, which are responsible for variations in prion disease phenotypes (prion strains). In this work, we use atomic force microscopy, FTIR spectroscopy and magic-angle spinning NMR to devise structural models of mouse prion protein fibrils prepared in three different denaturing conditions. We find that the fibril core region as well as the structure of its N- and C-terminal parts is almost identical between the three fibrils. In contrast, the central part differs in length of β-strands and the arrangement of charged residues. We propose that the denaturant ionic strength plays a major role in determining the structure of fibrils obtained in a particular condition by stabilizing fibril core interior-facing glutamic acid residues.

Prion disease in Indigenous Australians.

Indigenous Australians are at increased risk of developing dementia - Alzheimer disease and mixed dementia diagnoses are the most common. While prion diseases have been reported in Indigenous peoples of Papua New Guinea and the United States, the occurrence and phenotype of prion disease in Indigenous Australians is hitherto unreported. To report the incidence rate and clinical phenotype of Creutzfeldt-Jakob disease (CJD) in Indigenous Australians. Crude sporadic CJD (sCJD) incidence rates and indirect age standardisation of all CJD were assessed to calculate the standardised mortality ratio (SMR) of the Indigenous Australian population in comparison to the all-resident Australian population, along with analysis of clinical phenotypes. We report an illustrative case of an Indigenous Australian from regionally remote Western Australia dying from typical 'probable' sCJD 2 months after disease onset, with Australian National CJD Registry (ANCJDR) surveillance overall demonstrating eight Indigenous Australians dying from sCJD (five post-mortem confirmed, three classified as 'probable') with a clinical phenotype similar to non-indigenous people, including median age at death of 61 years (interquartile range IQR=16 years) and median duration of illness of 3 months (IQR=1.6 months). Indigenous Australians with sCJD were geographically dispersed throughout Australia. The calculated overall crude annual rate of sCJD in Indigenous Australians compared to the remainder of the Australian population was not significantly different (0-3.87/million for Indigenous Australians; 0.94-1.83/million for non-indigenous). The overall indirect age-standardised CJD mortality ratio for the indigenous population for the years 2006-2018 was 1.49 (95% CI, 0.75-2.98), also not significantly different to the all-resident Australian population. CJD occurs in Indigenous Australians with clinical phenotype and occurrence rates similar to non-Indigenous Australians. These findings contrast with a previous report where the incidence rate of CJD in a non-Australian indigenous population was reported to be decreased.

Prion protein glycans reduce intracerebral fibril formation and spongiosis in prion disease.

Posttranslational modifications (PTMs) are common among proteins that aggregate in neurodegenerative disease, yet how PTMs impact the aggregate conformation and disease progression remains unclear. By engineering knockin mice expressing prion protein (PrP) lacking 2 N-linked glycans (Prnp180Q/196Q), we provide evidence that glycans reduce spongiform degeneration and hinder plaque formation in prion disease. Prnp180Q/196Q mice challenged with 2 subfibrillar, non-plaque-forming prion strains instead developed plaques highly enriched in ADAM10-cleaved PrP and heparan sulfate (HS). Intriguingly, a third strain composed of intact, glycophosphatidylinositol-anchored (GPI-anchored) PrP was relatively unchanged, forming diffuse, HS-deficient deposits in both the Prnp180Q/196Q and WT mice, underscoring the pivotal role of the GPI-anchor in driving the aggregate conformation and disease phenotype. Finally, knockin mice expressing triglycosylated PrP (Prnp187N) challenged with a plaque-forming prion strain showed a phenotype reversal, with a striking disease acceleration and switch from plaques to predominantly diffuse, subfibrillar deposits. Our findings suggest that the dominance of subfibrillar aggregates in prion disease is due to the replication of GPI-anchored prions, with fibrillar plaques forming from poorly glycosylated, GPI-anchorless prions that interact with extracellular HS. These studies provide insight into how PTMs impact PrP interactions with polyanionic cofactors, and highlight PTMs as a major force driving the prion disease phenotype.

Co-occurrence of chronic traumatic encephalopathy and prion disease

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive traumatic brain injury (TBI). CTE is generally found in athletes participating in contact sports and military personnel exposed to explosive blasts but can also affect civilians. Clinically and pathologically, CTE overlaps with post-traumatic stress disorder (PTSD), a term mostly used in a clinical context. The histopathology of CTE is defined by the deposition of hyperphosphorylated tau protein in neurons and astrocytes preferentially with perivascular distribution and at the depths of the cortical sulci. In addition to hyperphosphorylated tau, other pathologic proteins are deposited in CTE, including amyloid β (Aβ), transactive response (TAR) DNA-binding protein 43 kDa (TDP-43) and α-synuclein. However, the coexistence of prion disease in CTE has not been observed. We report three cases of histopathologically validated CTE with co-existing sporadic prion disease. Two were identified in a cohort of 55 pathologically verified cases of CTE submitted to the CTE Center of Boston University. One was identified among brain tissues submitted to the National Prion Disease Pathology Surveillance Center of Case Western Reserve University. The histopathological phenotype and properties of the abnormal, disease-related prion protein (PrPD) of the three CTE cases were examined using lesion profile, immunohistochemistry, electrophoresis and conformational tests. Subjects with sporadic Creutzfeldt-Jakob disease (sCJD) matched for age, PrP genotype and PrPD type were used as controls. The histopathology phenotype and PrPD properties of the three CTE subjects showed no significant differences from their respective sCJD controls suggesting that recurring neurotrauma or coexisting CTE pathology did not detectably impact the prion disease phenotype and PrPD conformational characteristics. Based on the reported incidence of sporadic prion disease, the detection of two cases with sCJD in the CTE Center series of 55 CTE cases by chance alone would be highly unlikely (p = 8.93*10− 6). Nevertheless, examination of a larger cohort of CTE is required to conclusively determine whether the risk of CJD is significantly increased in patients with CTE.

Heparan sulfate chain length modulates the cellular targeting of prions in vivo

Prion diseases are fatal neurodegenerative disorders caused by the misfolding of the physiologically expressed prion protein into an insoluble form that accumulates as amorphous aggregates (subfibrillar prions) or amyloid fibers (fibrillar prions). Identical prion protein sequences can misfold into different conformational variants or strains that affect specific neural cell populations, leading to a wide variety of clinical signs and brain regions targeted. The mechanisms underlying the cell targeting of prion strains are unknown. Heparan sulfate (HS) molecules are glycosaminoglycans abundantly expressed in the brain and that profoundly vary in length and sulfation depending on the cell type. HS co‐localize with prion plaques of Creutzfeldt–Jakob disease (CJD), Gerstmann‐Sträussler‐Scheinker (GSS) syndrome, and sheep scrapie, and promote prion replication and fibril formation in vitro. Paradoxically, HS have been used to slow or even prevent prion formation in CJD patients and scrapie‐infected rodents. We hypothesize that the interaction of HS with prions is a major determinant underlying the selective cell vulnerability in prion diseases. Here we characterized the HS length that most effectively modulates the in vitro prion conversion into the aggregated state. We also determined how manipulating the HS chain length shifts the cell tropism of prion strains in vivo. While longer HS chain lengths led to more efficient prion conversion for subfibrillar strains (RML and ME7), intermediate lengths were more effective for the fibrillar strain mCWD. Ext1+/‐ mice expressing shorter HS molecules only altered prion disease phenotype when inoculated with the fibrillar prion mCWD, affecting the disease progression and neuropathology. Together these results suggest that the specific length of the HS together with the prion aggregate conformation determine the binding affinity of prions to HS, and underlie the specific cellular targeting in the CNS. These results have implications for other misfolding proteins such as amyloid‐β and α‐synuclein, which also interact with HS.Support or Funding InformationNIH, NINDS R01 grant 069566 Creutzfeldt–Jakob disease Foundation Fundación Ramón ArecesThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Variable tau accumulation in murine models with abnormal prion protein deposits

The conversion of cellular prion protein (PrP) into a misfolded isoform is central to the development of prion diseases. However, the heterogeneous phenotypes observed in prion disease may be linked with the presence of other misfolded proteins in the brain. While hyperphosphorylated tau (p.tau) is characteristic of Alzheimer's disease (AD), p.tau is also observed in human prion diseases. To explore this association in the absence of potential effects due to aging, drug treatment, agonal stage and postmortem delay we analyzed p.tau and PrP immunopositivity in mouse models. Analyses were performed on mice inoculated with prion agents, and mice with PrP amyloid in the absence of prion disease. We observed that p.tau was consistently present in animals with prion infectivity (models that transmit disease upon serial passage). In contrast, p.tau was very rarely observed or absent in mice with PrP amyloid plaques in the absence of prion replication. These data indicate that the formation of p.tau is not linked to deposition of misfolded PrP, but suggest that the interaction between replication of infectivity and host factors regulate the formation of p.tau and may contribute to the heterogeneous phenotype of prion diseases.

Host Determinants of Prion Strain Diversity Independent of Prion Protein Genotype.

Phenotypic diversity in prion diseases can be specified by prion strains in which biological traits are propagated through an epigenetic mechanism mediated by distinct PrP(Sc) conformations. We investigated the role of host-dependent factors on phenotypic diversity of chronic wasting disease (CWD) in different host species that express the same prion protein gene (Prnp). Two CWD strains that have distinct biological, biochemical, and pathological features were identified in transgenic mice that express the Syrian golden hamster (SGH) Prnp. The CKY strain of CWD had a shorter incubation period than the WST strain of CWD, but after transmission to SGH, the incubation period of CKY CWD was ∼150 days longer than WST CWD. Limited proteinase K digestion revealed strain-specific PrP(Sc) polypeptide patterns that were maintained in both hosts, but the solubility and conformational stability of PrP(Sc) differed for the CWD strains in a host-dependent manner. WST CWD produced PrP(Sc) amyloid plaques in the brain of the SGH that were partially insoluble and stable at a high concentration of protein denaturant. However, in transgenic mice, PrP(Sc) from WST CWD did not assemble into plaques, was highly soluble, and had low conformational stability. Similar studies using the HY and DY strains of transmissible mink encephalopathy resulted in minor differences in prion biological and PrP(Sc) properties between transgenic mice and SGH. These findings indicate that host-specific pathways that are independent of Prnp can alter the PrP(Sc) conformation of certain prion strains, leading to changes in the biophysical properties of PrP(Sc), neuropathology, and clinical prion disease. Prions are misfolded pathogenic proteins that cause neurodegeneration in humans and animals. Transmissible prion diseases exhibit a spectrum of disease phenotypes and the basis of this diversity is encoded in the structure of the pathogenic prion protein and propagated by an epigenetic mechanism. In the present study, we investigated prion diversity in two hosts species that express the same prion protein gene. While prior reports have demonstrated that prion strain properties are stable upon infection of the same host species and prion protein genotype, our findings indicate that certain prion strains can undergo dramatic changes in biological properties that are not dependent on the prion protein. Therefore, host factors independent of the prion protein can affect prion diversity. Understanding how host pathways can modify prion disease phenotypes may provide clues on how to alter prion formation and lead to treatments for prion, and other, human neurodegenerative diseases of protein misfolding.

Genome-wide association study of behavioural and psychiatric features in human prion disease.

Prion diseases are rare neurodegenerative conditions causing highly variable clinical syndromes, which often include prominent neuropsychiatric symptoms. We have recently carried out a clinical study of behavioural and psychiatric symptoms in a large prospective cohort of patients with prion disease in the United Kingdom, allowing us to operationalise specific behavioural/psychiatric phenotypes as traits in human prion disease. Here, we report exploratory genome-wide association analysis on 170 of these patients and 5200 UK controls, looking for single-nucleotide polymorphisms (SNPs) associated with three behavioural/psychiatric phenotypes in the context of prion disease. We also specifically examined a selection of candidate SNPs that have shown genome-wide association with psychiatric conditions in previously published studies, and the codon 129 polymorphism of the prion protein gene, which is known to modify various aspects of the phenotype of prion disease. No SNPs reached genome-wide significance, and there was no evidence of altered burden of known psychiatric risk alleles in relevant prion cases. SNPs showing suggestive evidence of association (P<10−5) included several lying near genes previously implicated in association studies of other psychiatric and neurodegenerative diseases. These include ANK3, SORL1 and a region of chromosome 6p containing several genes implicated in schizophrenia and bipolar disorder. We would encourage others to acquire phenotype data in independent cohorts of patients with prion disease as well as other neurodegenerative and neuropsychiatric conditions, to allow meta-analysis that may shed clearer light on the biological basis of these complex disease manifestations, and the diseases themselves.

Assessing proteinase K resistance of fish prion proteins in a scrapie-infected mouse neuroblastoma cell line.

The key event in prion pathogenesis is the structural conversion of the normal cellular protein, PrPC, into an aberrant and partially proteinase K resistant isoform, PrPSc. Since the minimum requirement for a prion disease phenotype is the expression of endogenous PrP in the host, species carrying orthologue prion genes, such as fish, could in theory support prion pathogenesis. Our previous work has demonstrated the development of abnormal protein deposition in sea bream brain, following oral challenge of the fish with natural prion infectious material. In this study, we used a prion-infected mouse neuroblastoma cell line for the expression of three different mature fish PrP proteins and the evaluation of the resistance of the exogenously expressed proteins to proteinase K treatment (PK), as an indicator of a possible prion conversion. No evidence of resistance to PK was detected for any of the studied recombinant proteins. Although not indicative of an absolute inability of the fish PrPs to structurally convert to pathogenic isoforms, the absence of PK-resistance may be due to supramolecular and conformational differences between the mammalian and piscine PrPs.

Proteomics analysis of amyloid and nonamyloid prion disease phenotypes reveals both common and divergent mechanisms of neuropathogenesis.

Prion diseases are a heterogeneous group of neurodegenerative disorders affecting various mammals including humans. Prion diseases are characterized by a misfolding of the host-encoded prion protein (PrPC) into a pathological isoform termed PrPSc. In wild-type mice, PrPC is attached to the plasma membrane by a glycosylphosphatidylinositol (GPI) anchor and PrPSc typically accumulates in diffuse nonamyloid deposits with gray matter spongiosis. By contrast, when mice lacking the GPI anchor are infected with the same prion inoculum, PrPSc accumulates in dense perivascular amyloid plaques with little or no gray matter spongiosis. In order to evaluate whether different host biochemical pathways were implicated in these two phenotypically distinct prion disease models, we utilized a proteomics approach. In both models, infected mice displayed evidence of a neuroinflammatory response and complement activation. Proteins involved in cell death and calcium homeostasis were also identified in both phenotypes. However, mitochondrial pathways of apoptosis were implicated only in the nonamyloid form, whereas metal binding and synaptic vesicle transport were more disrupted in the amyloid phenotype. Thus, following infection with a single prion strain, PrPC anchoring to the plasma membrane correlated not only with the type of PrPSc deposition but also with unique biochemical pathways associated with pathogenesis.

Persistent retroviral infection with MoMuLV influences neuropathological signature and phenotype of prion disease

A fundamental step in pathophysiology of prion diseases is the conversion of the host encoded prion protein (PrP(C)) into a misfolded isoform (PrP(Sc)) that accumulates mainly in neuronal but also non-neuronal tissues. Prion diseases are transmissible within and between species. In a subset of prion diseases, peripheral prion uptake and subsequent transport to the central nervous system are key to disease initiation. The involvement of retroviruses in this process has been postulated based on the findings that retroviral infections enhance the spread of prion infectivity and PrP(Sc) from cell to cell in vitro. To study whether retroviral infection influences the phenotype of prion disease or the spread of prion infectivity and PrP(Sc) in vivo, we developed a murine model with persistent Moloney murine leukemia retrovirus (MoMuLV) infection with and without additional prion infection. We investigated the pathophysiology of prion disease in MoMuLV and prion-infected mice, monitoring temporal kinetics of PrP(Sc) spread and prion infectivity, as well as clinical presentation. Unexpectedly, infection of MoMuLV challenged mice with prions did not change incubation time to clinical prion disease. However, clinical presentation of prion disease was altered in mice infected with both pathogens. This was paralleled by remarkably enhanced astrogliosis and pathognomonic astrocyte morphology in the brain of these mice. Therefore, we conclude that persistent viral infection might act as a disease modifier in prion disease.

Transmission of Chronic Wasting Disease Identifies a Prion Strain Causing Cachexia and Heart Infection in Hamsters

Chronic wasting disease (CWD) is an emerging prion disease of free-ranging and captive cervids in North America. In this study we established a rodent model for CWD in Syrian golden hamsters that resemble key features of the disease in cervids including cachexia and infection of cardiac muscle. Following one to three serial passages of CWD from white-tailed deer into transgenic mice expressing the hamster prion protein gene, CWD was subsequently passaged into Syrian golden hamsters. In one passage line there were preclinical changes in locomotor activity and a loss of body mass prior to onset of subtle neurological symptoms around 340 days. The clinical symptoms included a prominent wasting disease, similar to cachexia, with a prolonged duration. Other features of CWD in hamsters that were similar to cervid CWD included the brain distribution of the disease-specific isoform of the prion protein, PrPSc, prion infection of the central and peripheral neuroendocrine system, and PrPSc deposition in cardiac muscle. There was also prominent PrPSc deposition in the nasal mucosa on the edge of the olfactory sensory epithelium with the lumen of the nasal airway that could have implications for CWD shedding into nasal secretions and disease transmission. Since the mechanism of wasting disease in prion diseases is unknown this hamster CWD model could provide a means to investigate the physiological basis of cachexia, which we propose is due to a prion-induced endocrinopathy. This prion disease phenotype has not been described in hamsters and we designate it as the ‘wasting’ or WST strain of hamster CWD.

Genetic risk factors for variant Creutzfeldt–Jakob disease: a genome-wide association study

SummaryBackgroundHuman and animal prion diseases are under genetic control, but apart from PRNP (the gene that encodes the prion protein), we understand little about human susceptibility to bovine spongiform encephalopathy (BSE) prions, the causal agent of variant Creutzfeldt–Jakob disease (vCJD).MethodsWe did a genome-wide association study of the risk of vCJD and tested for replication of our findings in samples from many categories of human prion disease (929 samples) and control samples from the UK and Papua New Guinea (4254 samples), including controls in the UK who were genotyped by the Wellcome Trust Case Control Consortium. We also did follow-up analyses of the genetic control of the clinical phenotype of prion disease and analysed candidate gene expression in a mouse cellular model of prion infection.FindingsThe PRNP locus was strongly associated with risk across several markers and all categories of prion disease (best single SNP [single nucleotide polymorphism] association in vCJD p=2·5×10−17; best haplotypic association in vCJD p=1×10−24). Although the main contribution to disease risk was conferred by PRNP polymorphic codon 129, another nearby SNP conferred increased risk of vCJD. In addition to PRNP, one technically validated SNP association upstream of RARB (the gene that encodes retinoic acid receptor beta) had nominal genome-wide significance (p=1·9×10−7). A similar association was found in a small sample of patients with iatrogenic CJD (p=0·030) but not in patients with sporadic CJD (sCJD) or kuru. In cultured cells, retinoic acid regulates the expression of the prion protein. We found an association with acquired prion disease, including vCJD (p=5·6×10−5), kuru incubation time (p=0·017), and resistance to kuru (p=2·5×10−4), in a region upstream of STMN2 (the gene that encodes SCG10). The risk genotype was not associated with sCJD but conferred an earlier age of onset. Furthermore, expression of Stmn2 was reduced 30-fold post-infection in a mouse cellular model of prion disease.InterpretationThe polymorphic codon 129 of PRNP was the main genetic risk factor for vCJD; however, additional candidate loci have been identified, which justifies functional analyses of these biological pathways in prion disease.FundingThe UK Medical Research Council.

Elk with a long incubation prion disease phenotype have a unique PrPd profile

The transmissible spongiform encephalopathies (TSEs) invariably result in fatal neurodegeneration and accumulation of PrP, an abnormal form of the host prion protein PrP, encoded by the PRNP gene. A naturally occurring polymorphism (methionine/valine) at PRNP codon 129 is associated with variation in relative disease susceptibility, incubation time, clinical presentation, neuropathology, and/or PrP biochemical characteristics in a range of human TSEs. A methionine/leucine polymorphism at the corresponding site in the Rocky Mountain elk PRNP gene is associated with variation in relative susceptibility and incubation time in the cervid TSE chronic wasting disease. We now report that elk lacking the predisposing 132-methionine allele develop chronic wasting disease after a long incubation period and display a novel PrP folding pattern.

Different prion disease phenotypes result from inoculation of cattle with two temporally separated sources of sheep scrapie from Great Britain

BackgroundGiven the theoretical proposal that bovine spongiform encephalopathy (BSE) could have originated from sheep scrapie, this study investigated the pathogenicity for cattle, by intracerebral (i.c.) inoculation, of two pools of scrapie agents sourced in Great Britain before and during the BSE epidemic.Two groups of ten cattle were each inoculated with pools of brain material from sheep scrapie cases collected prior to 1975 and after 1990. Control groups comprised five cattle inoculated with sheep brain free from scrapie, five cattle inoculated with saline, and for comparison with BSE, naturally infected cattle and cattle i.c. inoculated with BSE brainstem homogenate from a parallel study. Phenotypic characterisation of the disease forms transmitted to cattle was conducted by morphological, immunohistochemical, biochemical and biological methods.ResultsDisease occurred in 16 cattle, nine inoculated with the pre-1975 inoculum and seven inoculated with the post-1990 inoculum, with four cattle still alive at 83 months post challenge (as at June 2006). The different inocula produced predominantly two different disease phenotypes as determined by histopathological, immunohistochemical and Western immunoblotting methods and biological characterisation on transmission to mice, neither of which was identical to BSE. Whilst the disease presentation was uniform in all scrapie-affected cattle of the pre-1975 group, the post-1990 inoculum produced a more variable disease, with two animals sharing immunohistochemical and molecular profile characteristics with animals in the pre-1975 group.ConclusionThe study has demonstrated that cattle inoculated with different pooled scrapie sources can develop different prion disease phenotypes, which were not consistent with the phenotype of BSE of cattle and whose isolates did not have the strain typing characteristics of the BSE agent on transmission to mice.

Characterization of two distinct prion strains derived from bovine spongiform encephalopathy transmissions to inbred mice.

Distinct prion strains can be distinguished by differences in incubation period, neuropathology and biochemical properties of disease-associated prion protein (PrP(Sc)) in inoculated mice. Reliable comparisons of mouse prion strain properties can only be achieved after passage in genetically identical mice, as host prion protein sequence and genetic background are known to modulate prion disease phenotypes. While multiple prion strains have been identified in sheep scrapie and Creutzfeldt-Jakob disease, bovine spongiform encephalopathy (BSE) is thought to be caused by a single prion strain. Primary passage of BSE prions to different lines of inbred mice resulted in the propagation of two distinct PrP(Sc) types, suggesting that two prion strains may have been isolated. To investigate this further, these isolates were subpassaged in a single line of inbred mice (SJL) and it was confirmed that two distinct prion strains had been identified. MRC1 was characterized by a short incubation time (110+/-3 days), a mono-glycosylated-dominant PrP(Sc) type and a generalized diffuse pattern of PrP-immunoreactive deposits, while MRC2 displayed a much longer incubation time (155+/-1 days), a di-glycosylated-dominant PrP(Sc) type and a distinct pattern of PrP-immunoreactive deposits and neuronal loss. These data indicate a crucial involvement of the host genome in modulating prion strain selection and propagation in mice. It is possible that multiple disease phenotypes may also be possible in BSE prion infection in humans and other animals.

The normal population distribution of PRNP codon 129 polymorphism.

The common prion protein gene (PRNP) codon 129 polymorphism modifies the susceptibility to and the phenotype of prion diseases. However, no truly representative normal population-based data, or data stratified according to age or gender are available on the distribution of this polymorphism. Allelic variation of codon 129 in three Finnish populations representing different age groups, and among Finnish, British and Irish blood donors were examined. The PRNP codon 129 genotype distribution in the total Finnish sample was 49% for methionine-methionine (MM), 42% for methionine-valine (MV) and 9% for valine-valine (VV), for the UK blood donors 42% for MM, 47% for MV and 11% for VV, and for the Irish blood donors 34% for MM, 56% for MV, and 10% for VV. The genotype frequencies were almost identical in all three Finnish populations of different ages, with no gender differences, and did not differ from corresponding figures for the Finnish blood donors. However, the PRNP codon 129 genotype distribution in Finland differed significantly from that of the British and the Irish blood donors and the previously published blood donor data on other Western Europeans and Americans.

Novel Missense Variants of Prion Protein in Creutzfeldt-Jakob Disease or Gerstmann-Sträussler Syndrome

We found 3 novel missense variants in the open reading frame of the prion protein (PrP) gene. The codon 105 point mutation (praline to leucine) was found on a codon 129 (Valine) PrP allele in 4 patients from 3 different Japanese families with Gerstmann-Sträussler syndrome. The codon 180 variant PrP (valine to isoleucine) was found in Creutzfeldt-Jakob disease (CJD) patients with a similar clinical course to that of codon 178 mutation. The codon 232 variant PrP (methionine to arginine) was documented in the CJD patients with typical clinical and pathological findings. These variant PrP molecules were not detected in 200 normal Japanese PrP alleles. PrP has a large repertoire of variant forms, and each primary structure of PrP corresponds to the distinct phenotype of prion diseases.