Human Sporadic Prion Diseases

Notari, Silvio

doi:10.1007/978-1-4614-5338-3_4

Cited by 5 publications

(2 citation statements)

References 63 publications

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“…The original classification of major sCJD subtypes based on histotype and PrP D characteristics has undergone recent revisions [2,11,12,27,32,43]. Sporadic CJDMM(MV)1 (a combination of -MM1 and -MV1, which share histotype and PrP D characteristics) as well as -MM2 (also referred to as MM2C) and -VV2, are seen as definitely distinct subtypes [5,18,19,32]. They are associated with PrP D variants that show distinct conformational and transmissible characteristics but have straightforward electrophoretic profiles of either PrP D type 1 or 2.…”

Section: Discussionmentioning

confidence: 99%

Two distinct conformers of PrPD type 1 of sporadic Creutzfeldt–Jakob disease with codon 129VV genotype faithfully propagate in vivo

Calì

Espinosa²,

Nemani

et al. 2021

acta neuropathol commun

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Current classifications of sporadic Creutzfeldt–Jakob disease (sCJD) identify five subtypes associated with different disease phenotypes. Most of these histopathological phenotypes (histotypes) co-distribute with distinct pairings of methionine (M)/valine (V) genotypes at codon 129 of the prion protein (PrP) gene and the type (1 or 2) of the disease-associated PrP (PrPD). Types 1 and 2 are defined by the molecular mass (~ 21 kDa and ~ 19 kDa, respectively) of the unglycosylated isoform of the proteinase K-resistant PrPD (resPrPD). We recently reported that the sCJDVV1 subtype (129VV homozygosity paired with PrPD type 1, T1) shows an electrophoretic profile where the resPrPD unglycosylated isoform is characterized by either one of two single bands of ~ 20 kDa (T120) and ~ 21 kDa (T121), or a doublet of ~ 21–20 kDa (T121−20). We also showed that T120 and T121 in sCJDVV have different conformational features but are associated with indistinguishable histotypes. The presence of three distinct molecular profiles of T1 is unique and raises the issue as to whether T120 and T121 represent distinct prion strains. To answer this question, brain homogenates from sCJDVV cases harboring each of the three resPrPD profiles, were inoculated to transgenic (Tg) mice expressing the human PrP-129M or PrP-129V genotypes. We found that T120 and T121 were faithfully replicated in Tg129V mice. Electrophoretic profile and incubation period of mice challenged with T121−20 resembled those of mice inoculated with T121 and T120, respectively. As in sCJDVV1, Tg129V mice challenged with T121 and T120 generated virtually undistinguishable histotypes. In Tg129M mice, T121 was not replicated while T120 and T121−20 generated a ~ 21–20 kDa doublet after lengthier incubation periods. On second passage, Tg129M mice incubation periods and regional PrP accumulation significantly differed in T120 and T121−20 challenged mice. Combined, these data indicate that T121 and T120 resPrPD represent distinct human prion strains associated with partially overlapping histotypes.

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Section: Discussionmentioning

confidence: 99%

Two distinct conformers of PrPD type 1 of sporadic Creutzfeldt–Jakob disease with codon 129VV genotype faithfully propagate in vivo

Calì

Espinosa²,

Nemani

et al. 2021

acta neuropathol commun

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“…The pathogenic mechanism based on the conformational conversion of PrP C into PrP Sc , which then acts as a seed, can conceptually accommodate not only PrP Sc accumulation and propagation in the affected subject, but also the potential transmission of the process from affected to non-affected subjects. Although the sporadic and inherited forms account for the majority of human prion diseases [ 24 ], less than 1% of the prion diseases is acquired from animals or humans via an infectious mechanism [ 7 ]. Within this group, iatrogenic CJD (iCJD) is of particular interest.…”

Section: Introductionmentioning

confidence: 99%

Iatrogenic Creutzfeldt-Jakob disease with Amyloid-β pathology: an international study

Calì

Cohen

Haїk

et al. 2018

acta neuropathol commun

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The presence of pathology related to the deposition of amyloid-β (Aβ) has been recently reported in iatrogenic Creutzfeldt-Jakob disease (iCJD) acquired from inoculation of growth hormone (GH) extracted from human cadaveric pituitary gland or use of cadaveric dura mater (DM) grafts.To investigate this phenomenon further, a cohort of 27 iCJD cases – 21 with adequate number of histopathological sections – originating from Australia, France, Italy, and the Unites States, were examined by immunohistochemistry, amyloid staining, and Western blot analysis of the scrapie prion protein (PrPSc), and compared with age-group matched cases of sporadic CJD (sCJD), Alzheimer disease (AD) or free of neurodegenerative diseases (non-ND).Cases of iCJD and sCJD shared similar profiles of proteinase K-resistant PrPSc with the exception of iCJD harboring the “MMi” phenotype. Cerebral amyloid angiopathy (CAA), either associated with, or free of, Thioflavin S-positive amyloid core plaques (CP), was observed in 52% of 21 cases of iCJD, which comprised 37.5% and 61.5% of the cases of GH- and DM-iCJD, respectively. If only cases younger than 54 years were considered, Aβ pathology affected 41%, 2% and 0% of iCJD, sCJD and non-ND, respectively. Despite the patients’ younger age CAA was more severe in iCJD than sCJD, while Aβ diffuse plaques, in absence of Aβ CP, populated one third of sCJD. Aβ pathology was by far most severe in AD. Tau pathology was scanty in iCJD and sCJD.In conclusion, (i) despite the divergences in the use of cadaveric GH and DM products, our cases combined with previous studies showed remarkably similar iCJD and Aβ phenotypes indicating that the occurrence of Aβ pathology in iCJD is a widespread phenomenon, (ii) CAA emerges as the hallmark of the Aβ phenotype in iCJD since it is observed in nearly 90% of all iCJD with Aβ pathology reported to date including ours, and it is shared by GH- and DM-iCJD, (iii) although the contributions to Aβ pathology of other factors, including GH deficiency, cannot be discounted, our findings increase the mounting evidence that this pathology is acquired by a mechanism resembling that of prion diseases.Electronic supplementary materialThe online version of this article (10.1186/s40478-017-0503-z) contains supplementary material, which is available to authorized users.

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