scholarly journals Sporadic Creutzfeldt-Jakob Disease: Prion Pathology in Medulla Oblongata—Possible Routes of Infection and Host Susceptibility

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Diego Iacono ◽  
Sergio Ferrari ◽  
Matteo Gelati ◽  
Gianluigi Zanusso ◽  
Sara Mariotto ◽  
...  
Keyword(s):  
Prion Protein ◽  
Environmental Exposure ◽  
Phenotypic Variability ◽  
Host Susceptibility ◽  
Motor Nucleus ◽  
Host Genotype ◽  
Dorsal Motor Nucleus ◽  
Jakob Disease ◽  
Medullary Nuclei ◽  
Codon 129

Sporadic Creutzfeldt-Jakob disease (sCJD), the most frequent human prion disorder, is characterized by remarkable phenotypic variability, which is influenced by the conformation of the pathologic prion protein and the methionine/valine polymorphic codon 129 of the prion protein gene. While the etiology of sCJD remains unknown, it has been hypothesized that environmental exposure to prions might occur through conjunctival/mucosal contact, oral ingestion, inhalation, or simultaneous involvement of the olfactory and enteric systems. We studied 21 subjects with definite sCJD to assess neuropathological involvement of the dorsal motor nucleus of the vagus and other medullary nuclei and to evaluate possible associations with codon 129 genotype and prion protein conformation. The present data show that prion protein deposition was detected in medullary nuclei of distinct sCJD subtypes, either valine homozygous or heterozygous at codon 129. These findings suggest that an “environmental exposure” might occur, supporting the hypothesis that external sources of contamination could contribute to sCJD in susceptible hosts. Furthermore, these novel data could shed the light on possible causes of sCJD through a “triple match” hypothesis that identify environmental exposure, host genotype, and direct exposure of specific anatomical regions as possible pathogenetic factors.

scholarly journals Phenotypic diversity of genetic Creutzfeldt–Jakob disease: a histo-molecular-based classification

2021 ◽  
Author(s):  
Simone Baiardi ◽  
Marcello Rossi ◽  
Angela Mammana ◽  
Brian S. Appleby ◽  
Marcelo A. Barria ◽  
...  
Keyword(s):  
Physicochemical Properties ◽  
Prion Protein ◽  
Phenotypic Diversity ◽  
Phenotypic Variability ◽  
Phenotypic Traits ◽  
Specific Effects ◽  
Jakob Disease ◽  
Phenotypic Features ◽  
Codon 129

AbstractThe current classification of sporadic Creutzfeldt–Jakob disease (sCJD) includes six major clinicopathological subtypes defined by the physicochemical properties of the protease-resistant core of the pathologic prion protein (PrPSc), defining two major PrPSc types (i.e., 1 and 2), and the methionine (M)/valine (V) polymorphic codon 129 of the prion protein gene (PRNP). How these sCJD subtypes relate to the well-documented phenotypic heterogeneity of genetic CJD (gCJD) is not fully understood. We analyzed molecular and phenotypic features in 208 individuals affected by gCJD, carrying 17 different mutations, and compared them with those of a large series of sCJD cases. We identified six major groups of gCJD based on the combination PrPSc type and codon 129 genotype on PRNP mutated allele, each showing distinctive histopathological characteristics, irrespectively of the PRNP associated mutation. Five gCJD groups, named M1, M2C, M2T, V1, and V2, largely reproduced those previously described in sCJD subtypes. The sixth group shared phenotypic traits with the V2 group and was only detected in patients carrying the E200K-129M haplotype in association with a PrPSc type of intermediate size (“i”) between type 1 and type 2. Additional mutation-specific effects involved the pattern of PrP deposition (e.g., a “thickened” synaptic pattern in E200K carriers, cerebellar “stripe-like linear granular deposits” in those with insertion mutations, and intraneuronal globular dots in E200K-V2 or -M”i”). A few isolated cases linked to rare PRNP haplotypes (e.g., T183A-129M), showed atypical phenotypic features, which prevented their classification into the six major groups. The phenotypic variability of gCJD is mostly consistent with that previously found in sCJD. As in sCJD, the codon 129 genotype and physicochemical properties of PrPSc significantly correlated with the phenotypic variability of gCJD. The most common mutations linked to CJD appear to have a variable and overall less significant effect on the disease phenotype, but they significantly influence disease susceptibility often in a strain-specific manner. The criteria currently used for sCJD subtypes can be expanded and adapted to gCJD to provide an updated classification of the disease with a molecular basis.

scholarly journals Extracellular Protein Aggregates Colocalization and Neuronal Dystrophy in Comorbid Alzheimer’s and Creutzfeldt–Jakob Disease: A Micromorphological Pilot Study on 20 Brains

2021 ◽  
Vol 22 (4) ◽  
pp. 2099
Author(s):  
Nikol Jankovska ◽  
Tomas Olejar ◽  
Radoslav Matej
Keyword(s):  
Prion Protein ◽  
Fluorescent Microscopy ◽  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Β Protein ◽  
Key Characteristics ◽  
Jakob Disease ◽  
Immunohistochemical Methods ◽  
Confocal Fluorescent Microscopy ◽  
Codon 129

Alzheimer’s disease (AD) and sporadic Creutzfeldt–Jakob disease (sCJD) are both characterized by extracellular pathologically conformed aggregates of amyloid proteins—amyloid β-protein (Aβ) and prion protein (PrPSc), respectively. To investigate the potential morphological colocalization of Aβ and PrPSc aggregates, we examined the hippocampal regions (archicortex and neocortex) of 20 subjects with confirmed comorbid AD and sCJD using neurohistopathological analyses, immunohistochemical methods, and confocal fluorescent microscopy. Our data showed that extracellular Aβ and PrPSc aggregates tended to be, in most cases, located separately, and “compound” plaques were relatively rare. We observed PrPSc plaque-like structures in the periphery of the non-compact parts of Aβ plaques, as well as in tau protein-positive dystrophic structures. The AD ABC score according to the NIA-Alzheimer’s association guidelines, and prion protein subtype with codon 129 methionine–valine (M/V) polymorphisms in sCJD, while representing key characteristics of these diseases, did not correlate with the morphology of the Aβ/PrPSc co-aggregates. However, our data showed that PrPSc aggregation could dominate during co-aggregation with non-compact Aβ in the periphery of Aβ plaques.

Distribution of vagal cardioinhibitory neurons in the medulla of the cat

1980 ◽  
Vol 238 (1) ◽  
pp. R57-R64 ◽  
Author(s):  
J. Ciriello ◽  
F. R. Calaresu
Keyword(s):  
Nucleus Tractus Solitarius ◽  
Border Region ◽  
Nucleus Ambiguus ◽  
Motor Nucleus ◽  
Dorsal Motor Nucleus ◽  
Antidromic Stimulation ◽  
Low Threshold ◽  
Vagal Bradycardia ◽  
Medullary Nuclei ◽  
Stimulation Of

Experiments were done in cats anesthetized with chloralose, paralyzed and artificially ventilated cats to obtain electrophysiological evidence on the medullary site of origin of vagal cardioinhibitory fibers. The regions of the nucleus ambiguus (AMB), dorsal motor nucleus of the vagus (DMV), nucleus tractus solitarius (NTS), and external cuneate nucleus (ECN) were systematically explored for units responding both to antidromic stimulation of the cardiac branches of the vagus (CBV) and to orthodromic stimulation of the carotid sinus and aortic depressor nerves. Eighty-six single units conforming to these criteria were found in the medulla: 30 in the AMB, 26 in the DMV, 12 in the NTS, 8 in the NTS-DMV border region, and 10 in the ECN. Antidromically evoked spikes had durations of 0.5--2.5 ms and followed stimulation frequencies of 20--500 Hz. The axons of these units conducted at velocities of 3.3--20.8 m/s. The specificity of activation of medullary units by cardioinhibitory fibers was tested in 11 units, which were found to respond consistently with an antidromic spike to stimulation of CBV but not to stimulation of the thoracic vagus. In eight spinal animals low threshold (less than 15 microA) sites eliciting vagal bradycardia were found in the same medullary nuclei where cardioinhibitory units had been located. These results indicate that vagal cardioinhibitory axons, originate in at least three medullary nuclei, the AMB, DMV, and NTS. Unit activity from the ECN may have been recorded from carioinhibitory fibers because of the short duration of the spike potentials.

scholarly journals The neuropathology of kuru and variant Creutzfeldt–Jakob disease

2008 ◽  
Vol 363 (1510) ◽  
pp. 3685-3687 ◽  
Author(s):  
Catriona A McLean
Keyword(s):  
Incubation Period ◽  
Prion Protein ◽  
Spongiform Encephalopathies ◽  
Genotype Analysis ◽  
Route Of Infection ◽  
Jakob Disease ◽  
Codon 129 ◽  
Selection Of

A comparison of the pathological profiles of two spongiform encephalopathies with a similar presumptive route of infection was performed. Archival kuru and recent variant Creutzfeldt–Jakob disease (vCJD) cases reveal distinct lesional differences, particularly with respect to prion protein, suggesting that the strain of agent is important in determining the phenotype. Genotype analysis of the polymorphism on codon 129 reveals (in conjunction with updated information from more kuru cases) that all three genotypes (VV, MV and MM (where M is methionine and V is valine)) are detected in kuru with some preference for MM homozygosity. The presence of valine does not therefore appear to determine peripheral selection of PrP CJD . vCJD remains restricted to date to MM homozygosity on codon 129. It remains to be determined whether this genotype is dictating a shorter incubation period.

scholarly journals Codon 129 polymorphism of prion protein gene in is not a risk factor for Alzheimer's disease

2013 ◽  
Vol 71 (7) ◽  
pp. 423-427 ◽  
Author(s):  
Jerusa Smid ◽  
Michele Christine Landemberger ◽  
Valéria Santoro Bahia ◽  
Vilma Regina Martins ◽  
Ricardo Nitrini
Keyword(s):  
Risk Factor ◽  
Cognitive Performance ◽  
Prion Protein ◽  
Protein Gene ◽  
Apoe Genotype ◽  
Genotype Distribution ◽  
Prion Protein Gene ◽  
Apolipoprotein E Gene ◽  
Jakob Disease ◽  
Codon 129

Interaction of prion protein and amyloid-b oligomers has been demonstrated recently. Homozygosity at prion protein gene (PRNP) codon 129 is associated with higher risk for Creutzfeldt-Jakob disease. This polymorphism has been addressed as a possible risk factor in Alzheimer disease (AD).ObjectiveTo describe the association between codon 129 polymorphisms and AD.MethodsWe investigated the association of codon 129 polymorphism of PRNP in 99 AD patients and 111 controls, and the association between this polymorphism and cognitive performance. Other polymorphisms of PRNP and additive effect of apolipoprotein E gene (ApoE) were evaluated.ResultsCodon 129 genotype distribution in AD 45.5% methionine (MM), 42.2% methionine valine (MV), 12.1% valine (VV); and 39.6% MM, 50.5% MV, 9.9% VV among controls (p>0.05). There were no differences of cognitive performance concerning codon 129. Stratification according to ApoE genotype did not reveal difference between groups.ConclusionCodon 129 polymorphism is not a risk factor for AD in Brazilian patients.

Accumulation of Pathogenic Prion Protein (PrPSc) in Nervous and Lymphoid Tissues of Sheep with Subclinical Scrapie

2003 ◽  
Vol 40 (2) ◽  
pp. 164-174 ◽  
Author(s):  
C. Ersdal ◽  
M. J. Ulvund ◽  
S. L. Benestad ◽  
M. A. Tranulis
Keyword(s):  
Lymph Node ◽  
Prion Protein ◽  
Spongiform Encephalopathy ◽  
Lymphoid Tissues ◽  
Motor Nucleus ◽  
Dorsal Motor Nucleus ◽  
The Central Nervous System ◽  
Natural Scrapie ◽  
First Time ◽  
The Brain

All sheep older than 1 year of age from a flock of the Rygja breed in which clinical scrapie was detected for the first time in two animals (4%) were examined for accumulation of pathogenic prion protein (PrPSc) by immunohistochemistry in the obex, the cerebellum, and the medial retrophayngeal lymph node. In addition, six lambs, 2–3 months old, all offspring of PrPSc-positive dams, were examined for PrPSc in the ileal Peyers' patch (IPP), the distal jejunal lymph node, the spleen, and the medial retropharyngeal lymph node (RPLN). In this flock, 35% (17/48) of the adult sheep showed accumulation of PrPSc, an eightfold increase compared with clinical disease. All positives carried susceptible PrP genotypes. Three sheep had deposits of PrPSc in the RPLN and not in the brain, suggesting that this organ, easily accessible at slaughter, is suitable for screening purposes. Two 7-year-old clinically healthy homozygous V136Q171 ewes showed sparse immunostaining in the central nervous system and may have been infected as adults. Further, two littermates, 86-days-old, showed PrPSc in the IPP. Interestingly, one of these lambs had the intermediate susceptible PrP genotype, VA136QR171. In addition to early immunolabeling in the dorsal motor nucleus of the vagal nerve, a few of the sheep had early involvement of the cerebellum. In fact, a 2-year-old sheep had sparse deposits of PrPSc in the cerebellum only. Because experimental bovine spongiform encephalopathy (BSE) in sheep seems to behave in a similar manner as natural scrapie, these results, particularly regarding spread of infectivity, may have implications for the handling of BSE should it be diagnosed in sheep.

scholarly journals Analysis of Conformational Stability of Abnormal Prion Protein Aggregates across the Spectrum of Creutzfeldt-Jakob Disease Prions

2016 ◽  
Vol 90 (14) ◽  
pp. 6244-6254 ◽  
Author(s):  
Maura Cescatti ◽  
Daniela Saverioni ◽  
Sabina Capellari ◽  
Fabrizio Tagliavini ◽  
Tetsuyuki Kitamoto ◽  
...  
Keyword(s):  
Prion Protein ◽  
Molecular Basis ◽  
Phenotypic Variability ◽  
Guanidine Hydrochloride ◽  
Conformational Stability ◽  
Protein Aggregates ◽  
Replication Efficiency ◽  
Prion Strains ◽  
Jakob Disease ◽  
Increasing Temperature

ABSTRACTThe wide phenotypic variability of prion diseases is thought to depend on the interaction of a host genotype with prion strains that have self-perpetuating biological properties enciphered in distinct conformations of the misfolded prion protein PrPSc. This concept is largely based on indirect approaches studying the effect of proteases or denaturing agents on the physicochemical properties of PrPScaggregates. Furthermore, most data come from studies on rodent-adapted prion strains, making current understanding of the molecular basis of strains and phenotypic variability in naturally occurring diseases, especially in humans, more limited. To fill this gap, we studied the effects of guanidine hydrochloride (GdnHCl) and heating on PrPScaggregates extracted from 60 sporadic Creutzfeldt-Jakob disease (CJD) and 6 variant CJD brains. While denaturation curves obtained after exposure of PrPScto increasing GdnHCl concentrations showed similar profiles among the 7 CJD types analyzed, PrPScexposure to increasing temperature revealed significantly different and type-specific responses. In particular, MM1 and VV2, the most prevalent and fast-replicating CJD types, showed stable and highly resistant PrPScaggregates, whereas VV1, a rare and slowly propagating type, revealed unstable aggregates that easily dissolved at low temperature. Taken together, our results indicate that the molecular interactions mediating the aggregation state of PrPSc, possibly enciphering strain diversity, are differently targeted by GdnHCl, temperature, and proteases. Furthermore, the detected positive correlation between the thermostability of PrPScaggregates and disease transmission efficiency makes inconsistent the proposed hypothesis that a decrease in conformational stability of prions results in an increase in their replication efficiency.IMPORTANCEPrion strains are defined as infectious isolates propagating distinctive phenotypic traits after transmission to syngeneic hosts. Although the molecular basis of prion strains is not fully understood, it is largely accepted that variations in prion protein conformation drive the molecular changes leading to the different phenotypes. In this study, we exposed abnormal prion protein aggregates encompassing the spectrum of human prion strains to both guanidine hydrochloride and thermal unfolding. Remarkably, while exposure to increasing temperature revealed significant strain-specific differences in the denaturation profile of the protein, treatment with guanidine hydrochloride did not. The findings suggest that thermal and chemical denaturation perturb the structure of prion protein aggregates differently. Moreover, since the most thermostable prion protein types were those associated with the most prevalent phenotypes and most rapidly and efficiently transmitting strains, the results suggest a direct correlation between strain replication efficiency and the thermostability of prion protein aggregates.

scholarly journals Type 1 protease resistant prion protein and valine homozygosity at codon 129 of PRNP identify a subtype of sporadic Creutzfeldt-Jakob disease

1999 ◽  
Vol 67 (5) ◽  
pp. 671-674 ◽  
Author(s):  
B. B Worrall ◽  
S. T Herman ◽  
S. Capellari ◽  
T. Lynch ◽  
S. Chin ◽  
...  
Keyword(s):  
Prion Protein ◽  
Jakob Disease ◽  
Codon 129
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