Genetic and pathological features encipher the phenotypic heterogeneity of Gerstmann-Sträussler-Scheinker disease.

OBJECTIVES: To elucidate and compare the genetic, clinical, ancillary diagnostic, and pathological characteristics across different Gerstmann-Sträussler-Scheinker disease (GSS) phenotypes and explore the underlying causes of the phenotypic heterogeneities. METHODS: The genetic, clinical, ancillary diagnostic, and pathological profiles of GSS patients reported in the literature were obtained and analyzed. Additionally, 3 patients with genetically confirmed GSS from our unit were included. Based on clinical presentation, patients were classified into typical GSS, Creutzfeldt-Jakob disease (CJD)-like GSS, GSS with dementia, and other categories. RESULTS: A total of 329 GSS cases were included with a 1.13:1 female-to-male ratio, median onset age 44, and median duration 4 years. Of the 294 categorized patients, 50.7% had typical GSS, 24.8% showed CJD-like GSS, and 16.3% presented with GSS with dementia. Clinical classification varied significantly based on genotype, with P102L more common in typical GSS and A117V prevalent in CJD-like GSS. Polymorphism at codon 129 has no effect on GSS phenotype, but the 129 M allele acts as a protective factor in GSS patients in Asia and North America. Moderate to severe spongiform degeneration and the presence of PK-resistant small fragments migrating at <11 kDa on electrophoretic gels along with PrP27-30 fragments were more prevalent in CJD-like GSS phenotype, while hyperphosphorylated tau protein co-deposition tends to be characteristic of typical GSS and GSS with dementia. CONCLUSION: This study reveals GSS's intricate nature, showing significant variations in clinical presentations, diagnostic findings, and pathological features. Mutation sites and pathological changes play crucial roles in determining the GSS clinical heterogeneity.

[Clinical characteristics and diagnostics of human spongiform encephalopathies: an update]. / Klinik und Diagnostik humaner spongiformer Enzephalopathien: ein Update.

Human spongiform encephalopathies are rare transmissible neurodegenerative diseases of the brain and the nervous system that are caused by misfolding of the physiological prion protein into a pathological form and its deposition in the central nervous system (CNS). Prion diseases include Creutzfeldt-Jakob disease (CJD, sporadic or familial), Gerstmann-Straussler-Scheinker syndrome (GSS) and fatal familial insomnia (FFI). Prion diseases can be differentiated into three etiological categories: spontaneous (sporadic CJD), inherited (familial CJD, FFI, and GSS) and acquired (variant CJD and iatrogenic CJD). Most cases occur sporadically. Prion diseases can lead to a variety of neurological symptoms and always have an inevitably fatal course. Cerebrospinal fluid analysis and magnetic resonance imaging (MRI) play a crucial role in the diagnostics of prion diseases and may facilitate an early and reliable clinical diagnosis. A causal treatment or specific therapeutic agents are not yet available. In general, a palliative therapeutic concept is indicated.

NGS study in a sicilian case series with a genetic diagnosis for Gerstmann-Sträussler-Scheinker syndrome (PRNP, p.P102L).

BACKGROUND: Gerstmann Sträussler Scheinker (GSS) is an inherited, invariably fatal prion disease. Like other human prion diseases, GSS is caused by missense mutations in the prion protein (PrP) gene (PRNP), and by the formation and overtime accumulation of the misfolded, pathogenic scrapie PrP (PrPSc). The first mutation identified in the PRNP gene, and the one blamed as the main cause of the disease, is c.C305T:p.P102L. METHODS AND RESULTS: The Sanger sequencing method was performed on the PRNP gene for the detection of c.C305T:p.P102L mutations in a cohort of 10 subjects; moreover, a study was carried out, using Next Generation Sequencing (NGS), by sequencing a group of genes related to amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), movement disorders and dementia which show a phenotypic profile similar to that of GSS. The results obtained from the study using NGS indicate the potential role of other genetic variants which could contribute to the various GSS phenotypes. CONCLUSIONS: In conclusion, we highlight the large clinical variability in subjects presenting with GSS and p.P102L, as well as the hypothesis that the mutation in PrP codon 102 alone is not sufficient to trigger the cardinal clinical signs of the disease; furthermore, we do not exclude the possibility that further genetic variants play a decisive role in the aspects of the various phenotypes with which GSS manifests itself.

Activation of Src family kinase ameliorates secretory trafficking in mutant prion protein cells.

Fatal familial insomnia (FFI), genetic Creutzfeldt-Jakob disease (gCJD), and Gerstmann-Sträussler-Scheinker (GSS) syndrome are neurodegenerative disorders linked to prion protein (PrP) mutations. The pathogenic mechanisms are not known, but increasing evidence points to mutant PrP misfolding and retention in the secretory pathway. We previously found that the D178N/M129 mutation associated with FFI accumulates in the Golgi of neuronal cells, impairing post-Golgi trafficking. In this study we further characterized the trafficking defect induced by the FFI mutation and tested the 178N/V129 variant linked to gCJD and a nine-octapeptide repeat insertion associated with GSS. We used transfected HeLa cells, embryonic fibroblasts and primary neurons from transgenic mice, and fibroblasts from carriers of the FFI mutation. In all these cell types, the mutant PrPs showed abnormal intracellular localizations, accumulating in the endoplasmic reticulum (ER) and Golgi. To test the efficiency of the membrane trafficking system, we monitored the intracellular transport of the temperature-sensitive vesicular stomatite virus glycoprotein (VSV-G), a well-established cargo reporter, and of endogenous procollagen I (PC-I). We observed marked alterations in secretory trafficking, with VSV-G accumulating mainly in the Golgi complex and PC-I in the ER and Golgi. A redacted version of mutant PrP with reduced propensity to misfold did not impair VSV-G trafficking, nor did artificial ER or Golgi retention of wild-type PrP; this indicates that both misfolding and intracellular retention were required to induce the transport defect. Pharmacological activation of Src family kinase (SFK) improved intracellular transport, suggesting that mutant PrP impairs secretory trafficking through corruption of SFK-mediated signaling.

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-ß 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 ß-strands, with the ß1 and ß8 strands, as well as the ß4 and ß9 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.

First familial cases of P102L Gerstmann-Sträussler-Scheinker syndrome in South Korea: diffusion-weighted imaging might reflect intrafamilial phenotypic variability.

INTRODUCTION: Gerstmann-Sträussler-Scheinker disease (GSS) is a rare genetic prion disease. Unlike sporadic Creutzfeldt-Jakob disease, GSS has diverse clinical phenotypes, including slowly progressive cerebellar ataxia. Due to this clinical feature and the extreme rarity of GSS, the disease can be misdiagnosed as hereditary cerebellar ataxia. CASE REPORT: We present the first familial cases of GSS in South Korea. Previously affected family members were misdiagnosed with hereditary cerebellar ataxia. Two siblings (patients #1 and #2) of this family were genetically diagnosed with P102L mutation GSS. Another sibling (patient #3) was not genetically confirmed, but based on the clinical course and diffusion-weighted imaging (DWI), the diagnosis of GSS will be certain. Despite the same genetic mutation, these siblings showed different clinical phenotypes of GSS. CONCLUSIONS: We genetically confirmed familial cases of GSS in South Korea. Although the disease is extremely rare, the PRNP gene test should be considered in undiagnosed autosomal dominant hereditary cerebellar ataxia. Phenotypical variability of GSS may be reflected in DWI of the early phase of the disease.

Prion Mutations in Republic of Republic of Korea, China, and Japan.

Prion gene (PRNP) mutations are associated with diverse disease phenotypes, including familiar Creutzfeldt-Jakob Disease (CJD), Gerstmann-Sträussler-Scheinker disease (GSS), and fatal familial insomnia (FFI). Interestingly, PRNP mutations have been reported in patients diagnosed with Alzheimer's disease, dementia with Lewy bodies, Parkinson's disease, and frontotemporal dementia. In this review, we describe prion mutations in Asian countries, including Republic of Republic of Korea, China, and Japan. Clinical phenotypes and imaging data related to these mutations have also been introduced in detail. Several prion mutations are specific to Asians and have rarely been reported in countries outside Asia. For example, PRNP V180I and M232R, which are rare in other countries, are frequently detected in Republic of Korea and Japan. PRNP T188K is common in China, and E200K is significantly more common among Libyan Jews in Israel. The A117V mutation has not been detected in any Asian population, although it is commonly reported among European GSS patients. In addition, V210I or octapeptide insertion is common among European CJD patients, but relatively rare among Asian patients. The reason for these differences may be geographical or ethical isolation. In terms of clinical phenotypes, V180I, P102L, and E200K present diverse clinical symptoms with disease duration, which could be due to other genetic and environmental influences. For example, rs189305274 in the ACO1 gene may be associated with neuroprotective effects in cases of V180I mutation, leading to longer disease survival. Additional neuroprotective variants may be possible in cases featuring the E200K mutation, such as KLKB1, KARS, NRXN2, LAMA3, or CYP4X1. E219K has been suggested to modify the disease course in cases featuring the P102L mutation, as it may result in the absence of prion protein-positive plaques in tissue stained with Congo red. However, these studies analyzed only a few patients and may be too preliminary. The findings need to be verified in studies with larger sample sizes or in other populations. It would be interesting to probe additional genetic factors that cause disease progression or act as neuroprotective factors. Further studies are needed on genetic modifiers working with prions and alterations from mutations.

Structure of Tau filaments in Prion protein amyloidoses.

In human neurodegenerative diseases associated with the intracellular aggregation of Tau protein, the ordered cores of Tau filaments adopt distinct folds. Here, we analyze Tau filaments isolated from the brain of individuals affected by Prion-Protein cerebral amyloid angiopathy (PrP-CAA) with a nonsense mutation in the PRNP gene that leads to early termination of translation of PrP (Q160Ter or Q160X), and Gerstmann-Sträussler-Scheinker (GSS) disease, with a missense mutation in the PRNP gene that leads to an amino acid substitution at residue 198 (F198S) of PrP. The clinical and neuropathologic phenotypes associated with these two mutations in PRNP are different; however, the neuropathologic analyses of these two genetic variants have consistently shown the presence of numerous neurofibrillary tangles (NFTs) made of filamentous Tau aggregates in neurons. We report that Tau filaments in PrP-CAA (Q160X) and GSS (F198S) are composed of 3-repeat and 4-repeat Tau isoforms, having a striking similarity to NFTs in Alzheimer disease (AD). In PrP-CAA (Q160X), Tau filaments are made of both paired helical filaments (PHFs) and straight filaments (SFs), while in GSS (F198S), only PHFs were found. Mass spectrometry analyses of Tau filaments extracted from PrP-CAA (Q160X) and GSS (F198S) brains show the presence of post-translational modifications that are comparable to those seen in Tau aggregates from AD. Cryo-EM analysis reveals that the atomic models of the Tau filaments obtained from PrP-CAA (Q160X) and GSS (F198S) are identical to those of the Tau filaments from AD, and are therefore distinct from those of Pick disease, chronic traumatic encephalopathy, and corticobasal degeneration. Our data support the hypothesis that in the presence of extracellular amyloid deposits and regardless of the primary amino acid sequence of the amyloid protein, similar molecular mechanisms are at play in the formation of identical Tau filaments.

An unusual familial dementia associated with G131V PRNP mutation.

BACKGROUND: Gerstmann-Struassler-Scheinker disease is one of the familial prion diseases secondary to mutations in the prion protein gene (PRNP). The clinical phenotype has a diverse spectrum and might show variation among cases with the same genotype. We report a patient with G131V mutation in the PRNP gene, who was initially considered to harbor familial Alzheimer's disease, based on the family history, clinical presentation and imaging findings. METHODS: A case with a G131V mutation in the PRNP gene is described, and the literature is reviewed. RESULTS: A 35-year-old man presented with personality changes, behavioral disturbances and cognitive complaints. A similar clinical phenotype was reported in the patient's father, a paternal uncle and a paternal aunt. In conjunction with the observation of mild cerebral atrophy on magnetic resonance imaging and hypometabolism in bilateral temporal and parietal lobes on positron-emission tomography studies, the diagnosis was initially considered as familial Alzheimer's disease. However, whole-exome sequencing of the index patient, confirmed with Sanger sequencing in his father and uncle, revealed the presence of a heterozygous G131V variant in the PRNP gene. CONCLUSION: To the best of our knowledge, this is the third report of a G131V mutation in the PRNP gene in the literature. Although ataxia and extrapyramidal findings accompanied dementia in patients reported in the previous literature, the members of the family in the present case primarily reported cognitive impairment, underscoring the importance of genetic evaluation in familial early-onset dementia patients, regardless of clinical and imaging features suggestive of alternative pathologies.

Isolation of infectious, non-fibrillar and oligomeric prions from a genetic prion disease.

Prions are transmissible agents causing lethal neurodegenerative diseases that are composed of aggregates of misfolded cellular prion protein (PrPSc). Despite non-fibrillar oligomers having been proposed as the most infectious prion particles, prions purified from diseased brains usually consist of large and fibrillar PrPSc aggregates, whose protease-resistant core (PrPres) encompasses the whole C-terminus of PrP. In contrast, PrPSc from Gerstmann-Sträussler-Scheinker disease associated with alanine to valine substitution at position 117 (GSS-A117V) is characterized by a small protease-resistant core, which is devoid of the C-terminus. We thus aimed to investigate the role of this unusual PrPSc in terms of infectivity, strain characteristics, and structural features. We found, by titration in bank voles, that the infectivity of GSS-A117V is extremely high (109.3 ID50 U/g) and is resistant to treatment with proteinase K (109.0 ID50 U/g). We then purified the proteinase K-resistant GSS-A117V prions and determined the amount of infectivity and PrPres in the different fractions, alongside the morphological characteristics of purified PrPres aggregates by electron microscopy. Purified pellet fractions from GSS-A117V contained the expected N- and C-terminally cleaved 7 kDa PrPres, although the yield of PrPres was low. We found that this low yield depended on the low density/small size of GSS-A117V PrPres, as it was mainly retained in the last supernatant fraction. All fractions were highly infectious, thus confirming the infectious nature of the 7 kDa PrPres, with infectivity levels that directly correlated with the PrPres amount detected. Finally, electron microscopy analysis of these fractions showed no presence of amyloid fibrils, but only very small and indistinct, non-fibrillar PrPresparticles were detected and confirmed to contain PrP via immunogold labelling. Our study demonstrates that purified aggregates of 7 kDa PrPres, spanning residues ∼90-150, are highly infectious oligomers that encode the biochemical and biological strain features of the original sample. Overall, the autocatalytic behaviour of the prion oligomers reveals their role in the propagation of neurodegeneration in patients with Gerstmann-Sträussler-Scheinker disease and implies that the C-terminus of PrPSc is dispensable for infectivity and strain features for this prion strain, uncovering the central PrP domain as the minimal molecular component able to encode infectious prions. These findings are consistent with the hypothesis that non-fibrillar prion particles are highly efficient propagators of disease and provide new molecular and morphological constraints on the structure of infectious prions.

Extracellular Prion Protein Aggregates in Nine Gerstmann-Sträussler-Scheinker Syndrome Subjects with Mutation P102L: A Micromorphological Study and Comparison with Literature Data.

Gerstmann-Sträussler-Scheinker syndrome (GSS) is a hereditary neurodegenerative disease characterized by extracellular aggregations of pathological prion protein (PrP) forming characteristic plaques. Our study aimed to evaluate the micromorphology and protein composition of these plaques in relation to age, disease duration, and co-expression of other pathogenic proteins related to other neurodegenerations. Hippocampal regions of nine clinically, neuropathologically, and genetically confirmed GSS subjects were investigated using immunohistochemistry and multichannel confocal fluorescent microscopy. Most pathognomic prion protein plaques were small (2-10 µm), condensed, globous, and did not contain any of the other investigated proteinaceous components, particularly dystrophic neurites. Equally rare (in two cases out of nine) were plaques over 50 µm having predominantly fibrillar structure and exhibit the presence of dystrophic neuritic structures; in one case, the plaques also included bulbous dystrophic neurites. Co-expression with hyperphosphorylated protein tau protein or amyloid beta-peptide (Aß) in GSS PrP plaques is generally a rare observation, even in cases with comorbid neuropathology. The dominant picture of the GSS brain is small, condensed plaques, often multicentric, while presence of dystrophic neuritic changes accumulating hyperphosphorylated protein tau or Aß in the PrP plaques are rare and, thus, their presence probably constitutes a trivial observation without any relationship to GSS development and progression.

Virus Infection, Genetic Mutations, and Prion Infection in Prion Protein Conversion.

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.

How an Infection of Sheep Revealed Prion Mechanisms in Alzheimer's Disease and Other Neurodegenerative Disorders.

Although it is not yet universally accepted that all neurodegenerative diseases (NDs) are prion disorders, there is little disagreement that Alzheimer's disease (AD), Parkinson's disease, frontotemporal dementia (FTD), and other NDs are a consequence of protein misfolding, aggregation, and spread. This widely accepted perspective arose from the prion hypothesis, which resulted from investigations on scrapie, a common transmissible disease of sheep and goats. The prion hypothesis argued that the causative infectious agent of scrapie was a novel proteinaceous pathogen devoid of functional nucleic acids and distinct from viruses, viroids, and bacteria. At the time, it seemed impossible that an infectious agent like the one causing scrapie could replicate and exist as diverse microbiological strains without nucleic acids. However, aggregates of a misfolded host-encoded protein, designated the prion protein (PrP), were shown to be the cause of scrapie as well as Creutzfeldt-Jakob disease (CJD) and Gerstmann-Sträussler-Scheinker syndrome (GSS), which are similar NDs in humans. This review discusses historical research on diseases caused by PrP misfolding, emphasizing principles of pathogenesis that were later found to be core features of other NDs. For example, the discovery that familial prion diseases can be caused by mutations in PrP was important for understanding prion replication and disease susceptibility not only for rare PrP diseases but also for far more common NDs involving other proteins. We compare diseases caused by misfolding and aggregation of APP-derived Aß peptides, tau, and α-synuclein with PrP prion disorders and argue for the classification of NDs caused by misfolding of these proteins as prion diseases. Deciphering the molecular pathogenesis of NDs as prion-mediated has provided new approaches for finding therapies for these intractable, invariably fatal disorders and has revolutionized the field.

A novel Gerstmann-Sträussler-Scheinker disease mutation defines a precursor for amyloidogenic 8 kDa PrP fragments and reveals N-terminal structural changes shared by other GSS alleles.

To explore pathogenesis in a young Gerstmann-Sträussler-Scheinker Disease (GSS) patient, the corresponding mutation, an eight-residue duplication in the hydrophobic region (HR), was inserted into the wild type mouse PrP gene. Transgenic (Tg) mouse lines expressing this mutation (Tg.HRdup) developed spontaneous neurologic syndromes and brain extracts hastened disease in low-expressor Tg.HRdup mice, suggesting de novo formation of prions. While Tg.HRdup mice exhibited spongiform change, PrP aggregates and the anticipated GSS hallmark of a proteinase K (PK)-resistant 8 kDa fragment deriving from the center of PrP, the LGGLGGYV insertion also imparted alterations in PrP's unstructured N-terminus, resulting in a 16 kDa species following thermolysin exposure. This species comprises a plausible precursor to the 8 kDa PK-resistant fragment and its detection in adolescent Tg.HRdup mice suggests that an early start to accumulation could account for early disease of the index case. A 16 kDa thermolysin-resistant signature was also found in GSS patients with P102L, A117V, H187R and F198S alleles and has coordinates similar to GSS stop codon mutations. Our data suggest a novel shared pathway of GSS pathogenesis that is fundamentally distinct from that producing structural alterations in the C-terminus of PrP, as observed in other prion diseases such as Creutzfeldt-Jakob Disease and scrapie.

Clinical Variability in P102L Gerstmann-Sträussler-Scheinker Syndrome.

Gerstmann-Sträussler-Scheinker syndrome (GSS) with the P102L mutation is a rare genetic prion disease caused by a pathogenic mutation at codon 102 in the prion protein gene. Cluster analysis encompassing data from 7 Czech patients and 87 published cases suggests the existence of 4 clinical phenotypes (typical GSS, GSS with areflexia and paresthesia, pure dementia GSS, and Creutzfeldt-Jakob disease-like GSS); GSS may be more common than previously estimated. In making a clinical diagnosis or progression estimates of GSS, magnetic resonance imaging and real-time quaking-induced conversion may be helpful, but the results should be evaluated with respect to the overall clinical context. ANN NEUROL 2019;86:643-652.

Early neurophysiological biomarkers and spinal cord pathology in inherited prion disease.

A common presentation of inherited prion disease is Gerstmann-Sträussler-Scheinker syndrome, typically presenting with gait ataxia and painful dysaesthesiae in the legs evolving over 2-5 years. The most frequent molecular genetic diagnosis is a P102L mutation of the prion protein gene (PRNP). There is no explanation for why this clinical syndrome is so distinct from Creutzfeldt-Jakob disease, and biomarkers of the early stages of disease have not been developed. Here we aimed, first, at determining if quantitative neurophysiological assessments could predict clinical diagnosis or disability and monitor progression and, second, to determine the neuropathological basis of the initial clinical and neurophysiological findings. We investigated subjects known to carry the P102L mutation in the longitudinal observational UK National Prion Monitoring Cohort study, with serial assessments of clinical features, peripheral nerve conduction, H and F components, threshold tracking and histamine flare and itch response and neuropathological examination in some of those who died. Twenty-three subjects were studied over a period of up to 12 years, including 65 neurophysiological assessments at the same department. Six were symptomatic throughout and six became symptomatic during the study. Neurophysiological abnormalities were restricted to the lower limbs. In symptomatic patients around the time of, or shortly after, symptom onset the H-reflex was lost. Lower limb thermal thresholds were at floor/ceiling in some at presentation, in others thresholds progressively deteriorated. Itch sensation to histamine injection was lost in most symptomatic patients. In six patients with initial assessments in the asymptomatic stage of the disease, a progressive deterioration in the ability to detect warm temperatures in the feet was observed prior to clinical diagnosis and the onset of disability. All of these six patients developed objective abnormalities of either warm or cold sensation prior to the onset of significant symptoms or clinical diagnosis. Autopsy examination in five patients (including two not followed clinically) showed prion protein in the substantia gelatinosa, spinothalamic tracts, posterior columns and nuclei and in the neuropil surrounding anterior horn cells. In conclusion, sensory symptoms and loss of reflexes in Gerstmann-Sträussler-Scheinker syndrome can be explained by neuropathological changes in the spinal cord. We conclude that the sensory symptoms and loss of lower limb reflexes in Gerstmann-Sträussler-Scheinker syndrome is due to pathology in the caudal spinal cord. Neuro-physiological measures become abnormal around the time of symptom onset, prior to diagnosis, and may be of value for improved early diagnosis and for recruitment and monitoring of progression in clinical trials.

Variable Protease-Sensitive Prionopathy Transmission to Bank Voles.

Variably protease-sensitive prionopathy (VPSPr), a recently described human sporadic prion disease, features a protease-resistant, disease-related prion protein (resPrPD) displaying 5 fragments reminiscent of Gerstmann-Sträussler-Scheinker disease. Experimental VPSPr transmission to human PrP-expressing transgenic mice, although replication of the VPSPr resPrPD profile succeeded, has been incomplete because of second passage failure. We bioassayed VPSPr in bank voles, which are susceptible to human prion strains. Transmission was complete; first-passage attack rates were 5%-35%, and second-passage rates reached 100% and survival times were 50% shorter. We observed 3 distinct phenotypes and resPrPD profiles; 2 imitated sporadic Creutzfeldt-Jakob disease resPrPD, and 1 resembled Gerstmann-Sträussler-Scheinker disease resPrPD. The first 2 phenotypes may be related to the presence of minor PrPD components in VPSPr. Full VPSPr transmission confirms permissiveness of bank voles to human prions and suggests that bank vole PrP may efficiently reveal an underrepresented native strain but does not replicate the complex VPSPr PrPD profile.

Anle138b prevents PrP plaque accumulation in Tg(PrP-A116V) mice but does not mitigate clinical disease.

Anle138b is an anti-aggregating compound previously shown to delay the onset of scrapie, a transmissible prion disease, although its in vivo efficacy against other prion disease subtypes has not been fully assessed. TgGSS mice that model Gerstmann-Sträussler-Scheinker disease (GSS) via expression of mouse PrPA116V accumulate PrP amyloid plaques in their brains and develop progressive ataxia leading to death in ~160 days. When allowed to feed on food pellets containing anle138b from weaning until death, the brains of TgGSS mice displayed significant reductions in PrP plaque burden, insoluble PrP, and proteinase K-resistant PrPSc at end stage, compared with TgGSS mice allowed to feed on placebo food pellets. Despite these effects on biological markers of disease, there was no difference in the onset of symptoms or the age at death between the two treatment groups. In contrast, scrapie-inoculated wild-type mice treated with anle138b survived nearly twice as long (254 days) as scrapie-inoculated mice fed placebo (~136 days). They also displayed greater reductions in insoluble and PK-resistant PrPSc than TgGSS mice. Although these results support an anti-aggregating effect of anle138b, the discordance in clinical efficacy noted between the two prion disease models tested underscores the pathophysiological differences between them and highlights the need to consider differences in susceptibilities among prion subtypes when assessing potential therapies for prion diseases.

Amyloid fibrils from the N-terminal prion protein fragment are infectious.

Recombinant C-terminally truncated prion protein PrP23-144 (which corresponds to the Y145Stop PrP variant associated with a Gerstmann-Sträussler-Scheinker-like prion disease) spontaneously forms amyloid fibrils with a parallel in-register ß-sheet architecture and ß-sheet core mapping to residues ∼112-139. Here we report that mice (both tga20 and wild type) inoculated with a murine (moPrP23-144) version of these fibrils develop clinical prion disease with a 100% attack rate. Remarkably, even though fibrils in the inoculum lack the entire C-terminal domain of PrP, brains of clinically sick mice accumulate longer proteinase K-resistant (PrPres) fragments of ∼17-32 kDa, similar to those observed in classical scrapie strains. Shorter, Gerstmann-Sträussler-Scheinker-like PrPres fragments are also present. The evidence that moPrP23-144 amyloid fibrils generated in the absence of any cofactors are bona fide prions provides a strong support for the protein-only hypothesis of prion diseases in its pure form, arguing against the notion that nonproteinaceous cofactors are obligatory structural components of all infectious prions. Furthermore, our finding that a relatively short ß-sheet core of PrP23-144 fibrils (residues ∼112-139) with a parallel in-register organization of ß-strands is capable of seeding the conversion of full-length prion protein to the infectious form has important implications for the ongoing debate regarding structural aspects of prion protein conversion and molecular architecture of mammalian prions.

Mutations in Prion Protein Gene: Pathogenic Mechanisms in C-Terminal vs. N-Terminal Domain, a Review.

Inherited mutations in the Prion protein (PrP), encoded by the PRNP gene, have been associated with autosomal dominant neurodegenerative disorders, such as Creutzfeldt-Jacob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), and Fatal Familial Insomnia (FFI). Notably, PRNP mutations have also been described in clinical pictures resembling other neurodegenerative diseases, such as frontotemporal dementia. Regarding the pathogenesis, it has been observed that these point mutations are located in the C-terminal region of the PRNP gene and, currently, the potential significance of the N-terminal domain has largely been underestimated. The purpose of this report is to review and provide current insights into the pathogenic mechanisms of PRNP mutations, emphasizing the differences between the C- and N-terminal regions and focusing, in particular, on the lesser-known flexible N-terminal, for which recent biophysical evidence has revealed a physical interaction with the globular C-terminal domain of the cellular prion protein (PrPC).