Prion Protein Gene Research Articles

No association of prion protein gene (PRNP) polymorphisms with susceptibility to the pandemic 2009 swine flu.

The pandemic2009 swineflu is a highly infectious respiratory disorder caused by H1N1 influenza A viruses. A recent study reported that knockout of the prion protein gene (PRNP) induced susceptibility and lethality in influenza A virus-infected mice. Thus, we examined the association between genetic variations of the PRNP gene and susceptibility to pandemic 2009 swine flu. We did not find an association between PRNP polymorphisms and susceptibility to pandemic 2009 swine flu. To the best of our knowledge, this was the first evaluation of the association between PRNP polymorphisms and vulnerability to pandemic 2009 swine flu.

Gerstmann-Sträussler-Scheinker Disease with F198S Mutation Induces Independent Tau and Prion Protein Pathologies in Bank Voles.

Gerstmann–Sträussler–Scheinker disease (GSS) is a rare genetic prion disease. A large GSS kindred linked to the serine-for-phenylalanine substitution at codon 198 of the prion protein gene (GSS-F198S) is characterized by conspicuous accumulation of prion protein (PrP)-amyloid deposits and neurofibrillary tangles. Recently, we demonstrated the transmissibility of GSS-F198S prions to bank vole carrying isoleucine at 109 PrP codon (BvI). Here we investigated: (i) the transmissibility of GSS-F198S prions to voles carrying methionine at codon 109 (BvM); (ii) the induction of hyperphosphorylated Tau (pTau) in two vole lines, and (iii) compared the phenotype of GSS-F198S-induced pTau with pTau induced in BvM following intracerebral inoculation of a familial Alzheimer’s disease case carrying Presenilin 1 mutation (fAD-PS1). We did not detect prion transmission to BvM, despite the high susceptibility of BvI previously observed. Immunohistochemistry established the presence of induced pTau depositions in vole brains that were not affected by prions. Furthermore, the phenotype of pTau deposits in vole brains was similar in GSS-F198S and fAD-PS1. Overall, results suggest that, regardless of the cause of pTau deposition and its relationship with PrPSc in GSS-F198S human-affected brains, the two components possess their own seeding properties, and that pTau deposition is similarly induced by GSS-F198S and fAD-PS1.

Amino Acid Substitution within Seven-Octapeptide Repeat Insertions in the Prion Protein Gene Associated with Short-Term Course.

The majority of seven-octapeptide repeat insertion (7-OPRI) carriers exhibit relatively early onset and a slowly progressive course. We have presented three cases of 7-OPRI, including two that are rapidly progressing, and compared the clinical and ancillary characteristics of the short-term and long-term disease course, as well as factors that influence disease course. The clinical and ancillary features of three new 7-OPRI patients in a Chinese pedigree were analyzed. Global data on 7-OPRI cases were then collected by reviewing the literature, and the cases were grouped according to clinical duration as per the WHO sCJD criteria, with a two-year cut-off. A Chinese pedigree has a glycine-to-glutamate substitution within the 7-OPRI insertion, which enhances the hydrophilicity of the prion protein. Two cases in this pedigree had a short disease course (consistent with the typical clinical and ancillary features of sCJD). In addition, the members of this pedigree had a later onset (p < 0.001) and shorter disease course (p < 0.001) compared to previously reported 7-OPRI cases with 129 cis-M and a similar age of onset and disease course to that of cases with 129 cis-V. The 7-OPRI cases with a shorter clinical course (n = 4) had a later onset (p = 0.021), higher rate of hyperintensity on MRI (p = 0.029) and higher frequency of 129 cis-V (p = 0.066) compared to those with a longer clinical course (n = 13). The clinical presentation of 7-OPRI is significantly heterogeneous. Codon 129 cis-V and amino acid substitution within repeat insertions are possible contributors to the short-term disease course of 7-OPRI.

Extrapolating the susceptibility of Eld’s deer (Rucervus eldii thamin) to chronic wasting disease from prion protein gene (PRNP) polymorphisms

Chronic wasting disease (CWD) is a prion disease of North American cervids. The transmission of CWD to endangered cervid species is of concern for captive breeding programs. Trans-species transmission could occur via direct contact with infected wild deer, or via prion contaminated fomites. Variation in the prion protein gene, PRNP, is associated with differences in CWD susceptibility among cervids. We therefore sequenced PRNP in 36 endangered Eld’s deer (Rucervus eldii thamin), detecting five synonymous and two non-synonymous SNPs. Three haplotypes were inferred, suggesting that genetic management in captive breeding programs has been effective at maintaining PRNP diversity. The haplotypes encoded two PrP protein variants. The more common Eld’s deer PrP variant encodes methionine at codon 208 and glutamine at codon 226. Because this protein variant is identical to a common PrP variant in white-tailed deer and mule deer and is especially common in white-tailed deer positive for CWD, we recommend reducing the frequency of this variant in the breeding stock, while implementing strict management practices to avoid exposure to wild North American cervids. The frequency of the other PrP variant, which differs from variants present in these North American cervids, was low. It has the potential to reduce susceptibility to CWD and thus could be increased in frequency. While PRNP haplotype frequencies should be shifted, genetic diversity should be maintained. Ultimately protein diversity may be protective should CWD infect the species, and trans-species polymorphisms are suggestive of past balancing selection and a potential fitness advantage for PRNP diversity.

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.

Genetic counseling for prion disease: Updates and best practices.

Prion disease is a rare, fatal, and often rapidly progressive neurodegenerative disease. Ten to fifteen percent of cases are caused by autosomal dominant gain-of-function variants in the prion protein gene, PRNP. Rarity and phenotypic variability complicate diagnosis, often obscuring family history and leaving families unprepared for the genetic implications of an index case. Several recent developments inspire this update in best practices for prion disease genetic counseling. A new prion-detection assay has transformed symptomatic diagnosis. Meanwhile, penetrance, age of onset, and duration of illness have been systematically characterized across PRNP variants in a global cohort. Clinically, the traditional genotype-phenotype correlation has weakened over time, and the term genetic prion disease may now better serve providers than the historical subtypes Creutzfeldt-Jakob disease, fatal familial insomnia, and Gerstmann-Sträussler-Scheinker disease. Finally, in the age of genetically targeted therapies, clinical trials for prion disease are being envisaged, and healthy at-risk individuals may be best positioned to benefit. Such individuals need to be able to access clinical services for genetic counseling and testing. Thus, this update on the genetics of prion disease and best practices for genetic counseling for this disease aims to provide the information needed to expand genetic counseling services.

Hereditary E200K mutation within the prion protein gene alters human iPSC derived cardiomyocyte function

Cardiomyopathy is a co-morbidity of some prion diseases including genetic disease caused by mutations within the PrP gene (PRNP). Although the cellular prion protein (PrP) has been shown to protect against cardiotoxicity caused by oxidative stress, it is unclear if the cardiomyopathy is directly linked to PrP dysfunction. We differentiated cardiomyocyte cultures from donor human induced pluripotent stem cells and found a direct influence of the PRNP E200K mutation on cellular function. The PRNP E200K cardiomyocytes showed abnormal function evident in the irregularity of the rapid repolarization; a phenotype comparable with the dysfunction reported in Down Syndrome cardiomyocytes. PRNP E200K cardiomyocyte cultures also showed increased mitochondrial superoxide accompanied by increased mitochondrial membrane potential and dysfunction. To confirm that the changes were due to the E200K mutation, CRISPR-Cas9 engineering was used to correct the E200K carrier cells and insert the E200K mutation into control cells. The isotype matched cardiomyocytes showed that the lysine expressing allele does directly influence electrophysiology and mitochondrial function but some differences in severity were apparent between donor lines. Our results demonstrate that cardiomyopathy in hereditary prion disease may be directly linked to PrP dysfunction.

First report of structural characteristics and polymorphisms of the prion protein gene in raccoon dogs: The possibility of prion disease-resistance.

Prion diseases are fatal degenerative encephalopathies caused by misfolded prion protein (PrPSc) converted from normal prion protein (PrPC). Previous studies have reported that genetic polymorphisms of the prion protein gene (PRNP) play a critical role in susceptibility to prion diseases. In addition, prion disease-resistant animals showed unique structural features of prion protein (PrP) related to species-specific amino acids. However, investigations of genetic polymorphisms of the PRNP gene and structural characteristics of PrP have not been performed in raccoon dogs thus far. We investigated genetic polymorphisms of PRNP in 87 raccoon dogs using amplicon sequencing and analyzed the genotype, allele, haplotype frequencies, and linkage disequilibrium (LD) using Haploview version 4.2. In addition, we performed phylogenetic analysis and multiple sequence alignment (MSA) using MEGA X version 10.1.8 and Clustal X version 2.1, respectively. We estimated the impact of raccoon dog and Canidae family-specific amino acids using PolyPhen-2, PROVEAN, and AMYCO. Furthermore, we analyzed the effect of raccoon dog and Canidae family-specific amino acids using the AlphaFold2 and Swiss-PdbViewer programs. We found 4 novel single nucleotide polymorphisms (SNPs) of the raccoon dog PRNP gene. In addition, the raccoon dog PrP showed 99.61% identity and the closest genetic distance to dog PrP. Among the substitutions of Canidae-specific amino acids with interspecific amino acids, D163N showed increased amyloidogenic propensity, and R181H showed alterations of hydrogen bonds. Furthermore, electrostatic potentials were changed according to the substitutions of D163N and R181H. By comparing PrP between raccoon dogs and raccoons, R168K and K224R were found to be related to changes in hydrogen bonds, and K224R altered the electrostatic potential of raccoon dog PrP. In the present study, we first reported 4 novel synonymous SNPs of the raccoon dog PRNP gene. We also identified that the PrP of raccoon dog has high homology (99.61%) with PrP of dog, which is a prion-resistant animal. In addition, raccoon dog PrP-specific amino acids are related to low amyloid propensity and inherent characteristics of 3D structure of raccoon dog PrP compared to the PrP of prion-susceptible species.

Variability in prion protein genotypes by spatial unit to inform susceptibility to chronic wasting disease

ABSTRACT Chronic wasting disease (CWD) is a fatal encephalopathy affecting North American cervids. Certain alleles in a host’s prion protein gene are responsible for reduced susceptibility to CWD. We assessed for the first time variability in the prion protein gene of elk (Cervus canadensis) present in Pennsylvania, United States of America, a reintroduced population for which CWD cases have never been reported. We sequenced the prion protein gene (PRNP) of 565 elk samples collected over 7 years (2014–2020) and found two polymorphic sites (codon 21 and codon 132). The allele associated with reduced susceptibility to CWD is present in the population, and there was no evidence of deviations from Hardy-Weinberg equilibrium in any of our sampling years (p-values between 0.14 and 1), consistent with the lack of selective pressure on the PRNP. The less susceptible genotypes were found in a frequency similar to the ones reported for elk populations in the states of Wyoming and South Dakota before CWD was detected. We calculated the proportion of less susceptible genotypes in each hunt zone in Pennsylvania as a proxy for their vulnerability to the establishment of CWD, and interpolated these results to obtain a surface representing expected proportion of the less susceptible genotypes across the area. Based on this analysis, hunt zones located in the southern part of our study area have a low proportion of less susceptible genotypes, which is discouraging for elk persistence in Pennsylvania given that these hunt zones are adjacent to the deer Disease Management Area 3, where CWD has been present since 2014.

Detection of chronic wasting disease in feces and recto-anal mucosal associated lymphoid tissues with RT-QuIC in a naturally infected farmed white-tailed deer herd.

Chronic wasting disease (CWD) is an infectious prion disease affecting the cervids, including white-tailed deer (WTD) (Odocoileus virginianus). CWD is typically diagnosed postmortem in farmed cervids by immunohistochemistry (IHC). Amplification-based detection methods are newer generation tests currently being evaluated to improve the detection of prion disease. In addition to improving sensitivity, antemortem detection by amplification assays is a focus for improving disease control and management. In this study, we evaluate the use of real-time quaking-induced conversion (RT-QuIC) to detect CWD in fecal and recto-anal mucosal-associated lymphoid tissue (RAMALT) samples from naturally infected farmed WTD herds at postmortem. We successfully detected the presence of CWD prions in WTD RAMALT with a specificity of 100% and a sensitivity of 85.7% (n = 71) and in feces with a specificity of 100% and a sensitivity of 60% (n = 69), utilizing RT-QuIC on samples collected postmortem. Seeding activity detected in RAMALT (15.3 ± 4.2%, n = 18) was much stronger than in feces (44.4 ± 4.2%, n = 15), as measured by cycle threshold (Ct) and rise in relative fluorescence in samples collected from the same WTD. Prion detection in the RAMALT (94.7%) and feces (70.5%) was highest when both obex and retropharyngeal lymph nodes (RPLNs) were positive for CWD via IHC. In the study group, we were also able to test prion protein gene variants and associated disease susceptibility. A majority of tested WTD were the CWD genotype (96 GG) and also harbored the highest percentage of positive animals (43.7%). The second highest population of WTD was the genotype 96 GS and had a CWD positivity rate of 37.5%. Each of these groups showed no difference in RAMALT or fecal detection of CWD.

Biochemical and Neuropathological Findings in a Creutzfeldt-Jakob Disease Patient with the Rare Val180Ile-129Val Haplotype in the Prion Protein Gene.

Genetic Creutzfeldt–Jakob disease (gCJD) associated with the V180I mutation in the prion protein (PrP) gene (PRNP) in phase with residue 129M is the most frequent cause of gCJD in East Asia, whereas it is quite uncommon in Caucasians. We report on a gCJD patient with the rare V180I-129V haplotype, showing an unusually long duration of the disease and a characteristic pathological PrP (PrPSc) glycotype. Family members carrying the mutation were fully asymptomatic, as commonly observed with this mutation. Neuropathological examination showed a lesion pattern corresponding to that commonly reported in Japanese V180I cases with vacuolization and gliosis of the cerebral cortexes, olfactory areas, hippocampus and amygdala. PrP was deposited with a punctate, synaptic-like pattern in the cerebral cortex, amygdala and olfactory tract. Western blot analyses of proteinase-K-resistant PrP showed the characteristic two-banding pattern of V180I gCJD, composed of mono- and un-glycosylated isoforms. In line with reports on other V180I cases in the literature, Real-Time Quaking Induced Conversion (RT-QuIC) analyses did not demonstrate the presence of seeding activity in the cerebrospinal fluid and olfactory mucosa, suggesting that this haplotype also may result in a reduced seeding efficiency of the pathological PrP. Further studies are required to understand the origin, penetrance, disease phenotype and transmissibility of 180I-129V haplotype in Caucasians.

Analysis of non-human primate models for evaluating prion disease therapeutic efficacy.

Prion disease is a fatal neurodegenerative disease caused by the conformational corruption of the prion protein (PrP), encoded by the prion protein gene (PRNP). While no disease-modifying therapy is currently available, genetic and pharmacological proofs of concept support development of therapies that lower PrP levels in the brain. In light of proposals for clinical testing of such drugs in presymptomatic individuals at risk for genetic prion disease, extensive nonclinical data are likely to be required, with extra attention paid to choice of animal models. Uniquely, the entire prion disease process can be faithfully modeled through transmission of human prions to non-human primates (NHPs), raising the question of whether NHP models should be used to assess therapeutic efficacy. Here we systematically aggregate data from N = 883 prion-inoculated animals spanning six decades of research studies. Using this dataset, we assess prion strain, route of administration, endpoint, and passage number to characterize the relationship of tested models to currently prevalent human subtypes of prion disease. We analyze the incubation times observed across diverse models and perform power calculations to assess the practicability of testing prion disease therapeutic efficacy in NHPs. We find that while some models may theoretically be able to support therapeutic efficacy studies, pilot studies would be required to confirm incubation time and attack rate before pivotal studies could be designed, cumulatively requiring several years. The models with the shortest and most tightly distributed incubation times are those with smaller brains and weaker homology to humans. Our findings indicate that it would be challenging to conduct efficacy studies in NHPs in a paradigm that honors the potential advantages of NHPs over other available models, on a timeframe that would not risk unduly delaying patient access to promising drug candidates.

Sporadic Creutzfeldt-Jakob disease VM1: phenotypic and molecular characterization of a novel subtype of human prion disease

The methionine (M)—valine (V) polymorphic codon 129 of the prion protein gene (PRNP) plays a central role in both susceptibility and phenotypic expression of sporadic Creutzfeldt-Jakob diseases (sCJD). Experimental transmissions of sCJD in humanized transgenic mice led to the isolation of five prion strains, named M1, M2C, M2T, V2, and V1, based on two major conformations of the pathological prion protein (PrPSc, type 1 and type 2), and the codon 129 genotype determining susceptibility and propagation efficiency. While the most frequent sCJD strains have been described in codon 129 homozygosis (MM1, MM2C, VV2) and heterozygosis (MV1, MV2K, and MV2C), the V1 strain has only been found in patients carrying VV. We identified six sCJD cases, 4 in Catalonia and 2 in Italy, carrying MV at PRNP codon 129 in combination with PrPSc type 1 and a new clinical and neuropathological profile reminiscent of the VV1 sCJD subtype rather than typical MM1/MV1. All patients had a relatively long duration (mean of 20.5 vs. 3.5 months of MM1/MV1 patients) and lacked electroencephalographic periodic sharp-wave complexes at diagnosis. Distinctive histopathological features included the spongiform change with vacuoles of larger size than those seen in sCJD MM1/MV1, the lesion profile with prominent cortical and striatal involvement, and the pattern of PrPSc deposition characterized by a dissociation between florid spongiform change and mild synaptic deposits associated with coarse, patch-like deposits in the cerebellar molecular layer. Western blot analysis of brain homogenates revealed a PrPSc type 1 profile with physicochemical properties reminiscent of the type 1 protein linked to the VV1 sCJD subtype. In summary, we have identified a new subtype of sCJD with distinctive clinicopathological features significantly overlapping with those of the VV1 subtype, possibly representing the missing evidence of V1 sCJD strain propagation in the 129MV host genotype.

Novel insertion/deletion polymorphisms and genetic features of the shadow of prion protein gene (SPRN) in dogs, a prion-resistant animal.

Prion diseases are fatal infectious neurodegenerative disorders that are induced by misfolded prion protein (PrPSc). Previous studies have reported that the shadow of prion protein (Sho) encoded by the shadow of prion protein gene (SPRN) plays a critical role in stimulating the conversion process of normal PrP (PrPC) into PrPSc, and genetic polymorphisms of the SPRN gene are significantly related to susceptibility to prion diseases. Recent studies have reported that dogs show prion resistance, and there have been several attempts to identify resistance factors to prion diseases in dogs. However, there has been no study of the canine SPRN gene thus far. We investigated genetic polymorphisms of the canine SPRN gene in 201 dogs using amplicon sequencing and compared the number of SPRN polymorphisms among prion-related species. In addition, we performed multiple sequence alignments of the amino acid sequences of Sho among prion-related species by ClustalW and analyzed the 3D structure of Sho using AlphaFold. Furthermore, we assessed the protein–protein interaction of canine PrP with canine Sho carrying wild-type and mutant alleles using HawkDock. We found four novel insertion/deletion polymorphisms of the SPRN gene in 201 dogs and identified a significant difference in the number of SPRN polymorphisms between prion-susceptible and prion-resistant animals. In addition, Sho has two α-helixes linked with the coil. Furthermore, we found different binding complexes and binding free energies between canine Sho and PrP according to SPRN polymorphisms. To the best of our knowledge, this is the first report of canine SPRN polymorphisms.

Genetic Polymorphism at 15 Codons of the Prion Protein Gene in 156 Goats from Romania.

Background: The variability of prion protein gene (PRNP) codons and the frequency of alleles (K222, D146, and S146) that appear to confer genetic resistance to classical scrapie are still unknown in several goat populations/breeds prevalent in Romania. This work aims to assess the genetic polymorphism at 15 PRNP codons in Romanian goat populations to inform the development of goat breeding programs for scrapie resistance. Methods: Whole blood and hair follicles from Carpathian (50), French Alpine (53), and Banat’s White (53) breed goats were sampled to extract genomic DNA for genetic analyses and Sanger sequencing. In the targeted goat groups, one classical scrapie-positive Banat’s White goat was included. Results: The codons without polymorphisms were G37G, W102W, N146N, R151R, S173S, and I218I. The following non-synonymous polymorphisms of PRNP were recorded: P110P, P110S, P110T, T110T, G127G, G127S, I142I, I142M, T142I, H143H, P143P, R143R, R154R, H154R, P168P, Q168Q, Q211Q, Q211R, Q222Q, H222Q, K222K, S240S, P240P, P240S, and S240P. Conclusions: PRNP polymorphism was recorded in 60% (9/15) of codons. The scrapie-positive Banat’s White goat had G37G, W102W, T110T, G127G, I142I, H143H, N146N, R151R, R154R, P168P, S173S, R211R, I218I, Q222Q, and S240S. The K222 allele had a frequency of 6% (3/50) in Carpathian, 9.43% (5/53) in Banat’s White, and 15.09% (8/53) in French Alpine. Therefore, the polymorphisms detected in this sample of Romanian goat breeds are too rare to design a breeding program at the current time.

PRNP gene polymorphism frequencies for comparing possible vulnerability to BSE in Chinese bovine population

Among the numerous transmissible spongiform encephalopathies (TSEs), bovine spongiform encephalopathy (BSE) is the most well-known TSEs. It is a potential Creutzfeldt–Jakob (CJD) disease mutation that can be transferred through cattle to humans. In several animals, the prion protein gene (PRNP) is recognized to take active part in TSE vulnerability or tolerance. Previous studies have found indels polymorphism in PRNP gene promoter and intron1 region linked to BSE vulnerability. It’s linked with 23 bp indels polymorphism in putative promoter and 12 bp indel in intron 1 of the PRNP gene. The aim of this study was to compare the allele, genotype and haplotype frequencies of PRNP indel polymorphisms in Zhongdian Yak (Bos grunniens) (YK), Zhongdian Yellow cattle (Bos taurus) (YC) and Zhongdian Yakow (Bos primigenius taurus × Bos grunniens) (PK) with worldwide reported healthy or affected BSE cattle, in order to assess their potential resistance to BSE. A comparison of Chinese bovine populations with healthy and BSE-affected German and Swiss cattle from globally was conducted, and result indicating significant difference (p < .001) between healthy and affected cattle. Additionally, as compared to prior studies with Chinese bovine population, the significant results were found. In this study, the allelic frequency D23 finding high deletion in all analyzed Chinese bovine species, and haplotype D12–D23 exhibited a less significant inclination toward susceptibility to BSE.

The First Evaluation of Proteinase K-Resistant Prion Protein (PrPSc) in Korean Appendix Specimens.

Background and Objectives: Prion diseases are fatal neurodegenerative disorders caused by the abnormal proteinase K-resistant prion protein (PrPSc). Since variant Creutzfeldt–Jakob disease (CJD) was first reported in the United Kingdom (UK) in 1996, the occurrence of variant CJD has been reported in over 10 countries. To date, variant CJD has not been reported in Korea. However, the E211K somatic mutation in the prion protein gene (PRNP), which is related to bovine spongiform encephalopathy (BSE), was reported in Korean Holstein cattle, and atypical BSE, which is supposed to be sporadic BSE, has been occurring in many countries, including Japan and the USA. These results suggest that BSE may occur naturally in Korea. Thus, we performed a preemptive PrPSc test in appendix specimens to diagnose variant CJD in a Korean population. Materials and Methods: In the present study, we investigated CJD-related mutations and polymorphisms of the PRNP gene and carried out an examination on PrPSc in appendix specimens of Korean patients after appendectomy. Results: In all Korean appendix specimens tested, PrPSc bands were not detected. Conclusion: To the best of our knowledge, this was the first evaluation of PrPSc in Korean appendix specimens.

Cryo-EM structures of prion protein filaments from Gerstmann–Sträussler–Scheinker disease

Prion protein (PrP) aggregation and formation of PrP amyloid (APrP) are central events in the pathogenesis of prion diseases. In the dominantly inherited prion protein amyloidosis known as Gerstmann–Sträussler–Scheinker (GSS) disease, plaques made of PrP amyloid are present throughout the brain. The c.593t > c mutation in the prion protein gene (PRNP) results in a phenylalanine to serine amino acid substitution at PrP residue 198 (F198S) and causes the most severe amyloidosis among GSS variants. It has been shown that neurodegeneration in this disease is associated with the presence of extracellular APrP plaques and neuronal intracytoplasmic Tau inclusions, that have been shown to contain paired helical filaments identical to those found in Alzheimer disease. Using cryogenic electron microscopy (cryo-EM), we determined for the first time the structures of filaments of human APrP, isolated post-mortem from the brain of two symptomatic PRNP F198S mutation carriers. We report that in GSS (F198S) APrP filaments are composed of dimeric, trimeric and tetrameric left-handed protofilaments with their protomers sharing a common protein fold. The protomers in the cross-β spines consist of 62 amino acids and span from glycine 80 to phenylalanine 141, adopting a previously unseen spiral fold with a thicker outer layer and a thinner inner layer. Each protomer comprises nine short β-strands, with the β1 and β8 strands, as well as the β4 and β9 strands, forming a steric zipper. The data obtained by cryo-EM provide insights into the structural complexity of the PrP filament in a dominantly inherited human PrP amyloidosis. The novel findings highlight the urgency of extending our knowledge of the filaments' structures that may underlie distinct clinical and pathologic phenotypes of human neurodegenerative diseases.

Novel Polymorphisms and Genetic Characteristics of the Prion Protein Gene in Pheasants.

Transmissible spongiform encephalopathies (TSEs) also known as prion diseases, are fatal neurodegenerative diseases. Prion diseases are caused by abnormal prion protein (PrPSc) derived from normal prion protein (PrPC), which is encoded by the prion protein gene (PRNP). Prion diseases have been reported in several mammals. Notably, chickens, one species of bird, have not been reported to develop prion diseases and showed resistance to bovine spongiform encephalopathy (BSE) infection. However, genetic polymorphisms of the PRNP gene and protein structure of the prion protein (PrP) related to vulnerability to prion diseases have not been investigated in pheasants, another species of bird. We performed amplicon sequencing of the pheasant PRNP gene to identify genetic polymorphisms in 148 pheasants. We analyzed the genotype, allele and haplotype frequencies of the pheasant PRNP polymorphisms. In addition, we evaluated the effect of genetic polymorphisms of the pheasant PRNP gene on pheasant PrP by the AMYCO, PROVEAN, PolyPhen-2 and PANTHER softwares. Furthermore, we compared the amino acid sequences of tandem repeat domains and secondary and tertiary structures of prion proteins (PrPs) among several animals. Finally, we investigated the impact of non-synonymous single nucleotide polymorphisms (SNPs) on hydrogen bonds and tertiary structures of pheasant PrP by Swiss PDB viewer software. We identified 34 novel genetic polymorphisms of the pheasant PRNP gene including 8 non-synonymous SNPs and 6 insertion/deletion polymorphisms. Among the non-synonymous SNPs, the L23F, G33C and R177Q SNPs showed that they could have a deleterious effect on pheasant PrP. In addition, the R177Q SNP was predicted to show an increase in amyloid propensity and a reduction in hydrogen bonds of pheasant PrP. Among the insertion/deletion polymorphisms, c.163_180delAACCCGGGGTATCCCCAC showed that it could have a detrimental effect on pheasant PrP. Furthermore, secondary and tertiary structures of pheasant PrP were predicted to have structures similar to those of chicken PrP. To the best of our knowledge, this is the first study on genetic polymorphisms of the pheasant PRNP gene.

Genetic prion diseases presenting as frontotemporal dementia: clinical features and diagnostic challenge

BackgroundTo elucidate the clinical and ancillary features of genetic prion diseases (gPrDs) presenting with frontotemporal dementia (FTD) to aid early identification.MethodsGlobal data of gPrDs presenting with FTD caused by prion protein gene mutations were collected from literature review and our records. Fifty-one cases of typical FTD and 136 cases of prion diseases admitted to our institution were included as controls. Clinical and ancillary data of the different groups were compared.ResultsForty-nine cases of gPrDs presenting with FTD were identified. Compared to FTD or prion diseases, gPrDs presenting with FTD were characterized by earlier onset age (median 45 vs. 61/60 years, P < 0.001, P < 0.001) and higher incidence of positive family history (81.6% vs. 27.5/13.2%, P < 0.001, P < 0.001). Furthermore, GPrDs presenting with FTD exhibited shorter duration (median 5 vs. 8 years) and a higher rate of parkinsonism (63.7% vs. 9.8%, P < 0.001), pyramidal signs (39.1% vs. 7.8%, P = 0.001), mutism (35.9% vs. 0%, P < 0.001), seizures (25.8% vs. 0%, P < 0.001), myoclonus (22.5% vs. 0%, P < 0.001), and hyperintensity on MRI (25.0% vs. 0, P < 0.001) compared to FTD. Compared to prion diseases, gPrDs presenting with FTD had a longer duration of symptoms (median 5 vs. 1.1 years, P < 0.001), higher rates of frontotemporal atrophy (89.7% vs. 3.3%, P < 0.001), lower rates of periodic short-wave complexes on EEG (0% vs. 30.3%, P = 0.001), and hyperintensity on MRI (25.0% vs. 83.0%, P < 0.001). The frequency of codon 129 Val allele in gPrDs presenting with FTD was significantly higher than that reported in the literature for gPrDs in the Caucasian and East Asian populations (33.3% vs. 19.2%/8.0%, P = 0.005, P < 0.001).ConclusionsGPrDs presenting with FTD are characterized by early-onset, high incidence of positive family history, high frequency of the Val allele at codon 129, overlapping symptoms with prion disease and FTD, and ancillary features closer to FTD. PRNP mutations may be a rare cause in the FTD spectrum, and PRNP genotyping should be considered in patients with these features.