Variably protease‐sensitive prionopathy presenting within ALS/FTD spectrum

Vicente-Pascual, Mikel; Rossi, Marcello; Gámez, Josep; Lladó, Albert; Valls, J.; Grau‐Rivera, Oriol; Polo, Rainiero Ávila; Llorens, Franc; Zerr, Inga; Ferrer, Isidre; Nos, Carlos; Parchi, Piero; Sánchez‐Valle, Raquel; Gelpí, Ellen

doi:10.1002/acn3.632

Cited by 11 publications

(22 citation statements)

References 9 publications

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“…Thus, VPSPr can be regarded as a sporadic variant of GSS [25]. Interestingly, VPSPr PrP Sc preparations sometimes show fragments of high molecular mass similar to those observed in CJD type 2 [27,28]. This shows possibility of conversion of GSS-type core into CJD-type.…”

Section: Prp Sc Coresmentioning

confidence: 82%

Proteinase K resistant cores of prions and amyloids

Kushnirov

Dergalev

Alexandrov

2019

Prion

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Amyloids and their infectious subset, prions, represent fibrillary aggregates with regular structure. They are formed by proteins that are soluble in their normal state. In amyloid form, all or part of the polypeptide sequence of the protein is resistant to treatment with proteinase K (PK). Amyloids can have structural variants, which can be distinguished by the patterns of their digestion by PK. In this review, we describe and compare studies of the resistant cores of various amyloids from different organisms. These data provide insight into the fine structure of amyloids and their variants as well as raise interesting questions, such as those concerning the differences between amyloids obtained ex vivo and in vitro, as well as the manner in which folding of one region of the amyloid can affect other regions. ARTICLE HISTORY

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Section: Prp Sc Coresmentioning

confidence: 82%

Proteinase K resistant cores of prions and amyloids

Kushnirov

Dergalev

Alexandrov

2019

Prion

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“…Furthermore, GSS brains occasionally show PrP Sc fragments of higher molecular weight resembling the primary PrP Sc species found in CJD and FI, such as PrP Sc types 1 and 2 (Figure 1). Similarly, recent studies documented a regional variability of PrP Sc properties also in VPSPr, including the presence of a fully glycosylated (i.e., comprising the diglycosylated form) CJD-like 19-kDa PrP Sc fragment in some cases [61,62]. These findings not only corroborate the similarities between GSS and VPSPr, but also indicate that CJD/FI and GSS/VPSPr belong to a disease spectrum rather than being considered as separate disorders with different pathogenesis.…”

Section: Molecular Basis Of Phenotypic Variability and Disease Submentioning

confidence: 98%

Understanding Prion Strains: Evidence from Studies of the Disease Forms Affecting Humans

Rossi

Baiardi

Parchi

2019

Viruses

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Prion diseases are a unique group of rare neurodegenerative disorders characterized by tissue deposition of heterogeneous aggregates of abnormally folded protease-resistant prion protein (PrPSc), a broad spectrum of disease phenotypes and a variable efficiency of disease propagation in vivo. The dominant clinicopathological phenotypes of human prion disease include Creutzfeldt–Jakob disease, fatal insomnia, variably protease-sensitive prionopathy, and Gerstmann–Sträussler–Scheinker disease. Prion disease propagation into susceptible hosts led to the isolation and characterization of prion strains, initially operatively defined as “isolates” causing diseases with distinctive characteristics, such as the incubation period, the pattern of PrPSc distribution, and the regional severity of neuropathological changes after injection into syngeneic hosts. More recently, the structural basis of prion strains has been linked to amyloid polymorphs (i.e., variant amyloid protein conformations) and the concept extended to all protein amyloids showing polymorphic structures and some evidence of in vivo or in vitro propagation by seeding. Despite the significant advances, however, the link between amyloid structure and disease is not understood in many instances. Here we reviewed the most significant contributions of human prion disease studies to current knowledge of the molecular basis of phenotypic variability and the prion strain phenomenon and underlined the unsolved issues from the human disease perspective.

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“…The clinical phenotype is more often consistent with an AD‐type or frontotemporal‐type of dementia, sometimes associated with atypical parkinsonism. However, atypical presentations may also occur as in two recently reported patients with autopsy‐confirmed VPSPr who received a clinical diagnosis of amyotrophic lateral sclerosis . Spongiform change is characterized by non‐confluent vacuoles of intermediate size [ie, larger than in sCJDMM(V)1, but smaller than in sCJDMM2C] and the lesion profile by a predominant involvement of cerebral cortices, striatum and thalamus, while the cerebellum is variably affected and the hippocampus relatively spared.…”

Section: Phenotypic Spectrum and Classification Of Disease Subtypesmentioning

confidence: 98%

Recent advances in the histo‐molecular pathology of human prion disease

et al. 2019

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Prion diseases are progressive neurodegenerative disorders affecting humans and other mammalian species. The term prion, originally put forward to propose the concept that a protein could be infectious, refers to PrP Sc , a misfolded isoform of the cellular prion protein (PrP C ) that represents the pathogenetic hallmark of these disorders. The discovery that other proteins characterized by misfolding and seeded aggregation can spread from cell to cell, similarly to PrP Sc , has increased interest in prion diseases. Among neurodegenerative disorders, however, prion diseases distinguish themselves for the broader phenotypic spectrum, the fastest disease progression and the existence of infectious forms that can be transmitted through the exposure to diseased tissues via ingestion, injection or transplantation. The main clinicopathological phenotypes of human prion disease include Creutzfeldt-Jakob disease, by far the most common, fatal insomnia, variably protease-sensitive prionopathy, and Gerstmann-Sträussler-Scheinker disease. However, clinicopathological manifestations extend even beyond those predicted by this classification. Because of their transmissibility, the phenotypic diversity of prion diseases can also be propagated into syngenic hosts as prion strains with distinct characteristics, such as incubation period, pattern of PrP Sc distribution and regional severity of histopathological changes in the brain. Increasing evidence indicates that different PrP Sc conformers, forming distinct ordered aggregates, encipher the phenotypic variants related to prion strains. In this review, we summarize the most recent advances concerning the histo-molecular pathology of human prion disease focusing on the phenotypic spectrum of the disease including co-pathologies, the characterization of prion strains by experimental transmission and their correlation with the physicochemical properties of PrP Sc aggregates.

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Variably protease‐sensitive prionopathy presenting within ALS/FTD spectrum

Cited by 11 publications

References 9 publications

Proteinase K resistant cores of prions and amyloids

Proteinase K resistant cores of prions and amyloids

Understanding Prion Strains: Evidence from Studies of the Disease Forms Affecting Humans

Recent advances in the histo‐molecular pathology of human prion disease

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