Intracerebral distribution of the abnormal isoform of the prion protein in sporadic Creutzfeldt-Jakob disease and fatal insomnia

Parchi, Piero; Capellari, Sabina

doi:10.1002/1097-0029(20000701)50:1<16::aid-jemt4>3.0.co;2-y

Cited by 30 publications

(24 citation statements)

References 57 publications

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“…Loss of granule cells, spongiosis in the granular and molecular layers, and variable involvement of Purkinje cells with occasional formation of axonal torpedoes are the classical abnormalities. Abnormal PrP deposition is evident [7] as well as ultrastructural changes, including reduction of dendritic arbors, loss of dendritic spines, and hypertrophy of dendritic branches of Purkinje cells [24]. Transgenic mice expressing the mutated PrP with an insertion in the octarepeat domain of the prion protein display atrophy of the cerebellum, with reduction in the Fig.…”

Section: Discussionmentioning

confidence: 61%

“…Basal ganglia, thalamus, cerebellum, and brainstem are also variably involved [3,4]. The cerebral distribution of the abnormal protein was reported to be primarily cortical, with significant concentrations also in basal ganglia and cerebellum [5,6] A recent review [7] reported that the highest amounts of PrP Sc were found in all four cortical lobes, entorhinal cortex, striatum, thalamus, and cerebellum, in the most common phenotype, but emphasized the phenotypic heterogeneity, which appears to depend on the interaction between the prion strain and the host genotype. PrP Sc plaques are most common in the cerebellum [6].…”

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confidence: 99%

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MRI Detection of the Cerebellar Syndrome in Creutzfeldt–Jakob Disease

et al. 2009

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Creutzfeldt-Jakob Disease (CJD) is characterized by bilateral basal ganglia hyperintensities on T2W and diffusion-weighted imaging (DWI) magnetic resonance imaging (MRI) scans, consistent with its extrapyramidal neurological manifestations. MRI is diagnostically uninformative about the cerebellar symptoms, equally prominent in CJD. This study was undertaken to explain this apparent paradox. Eleven CJD patients with definite cerebellar or brain stem symptoms were selected from a large prospective study, as well as 11 healthy controls matched for age and gender. All subjects participated in a standardized MRI protocol, including SPGR, fluid-attenuated inversion recovery (FLAIR), DWI and diffusion tensor imaging (DTI). All subjects underwent detailed examination by a neurologist blinded to the radiological findings, who predicted the expected site of cerebral abnormalities. MRI showed good sensitivity for the abnormalities predicted in the cortex (80-90%) and basal ganglia (100%). None of the standard MRI sequences, including DWI, DTI, and FLAIR, revealed any tissue abnormalities in cerebellum or brain stem. Apparent diffusion coefficient (ADC) values, however, were substantially and significantly elevated in several cerebellar structures, where also the volumetric (VBM) analysis revealed elevated cerebrospinal fluid volume, suggesting focal cerebellar atrophy in these CJD patients. In patients with CJD, DWI appears sensitive to the reduced diffusivity in cortex and basal ganglia but insensitive to cerebellar involvement. We propose that the radiological hallmark of cerebellar pathology in CJD is atrophy, revealed quantitatively by both VBM and elevated diffusivity, which is identifiable on ADC maps but poorly visualized in nonquantitative DWI images.

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Section: Discussionmentioning

confidence: 61%

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confidence: 99%

MRI Detection of the Cerebellar Syndrome in Creutzfeldt–Jakob Disease

et al. 2009

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“…PrP-res fragments truncated at the N terminus but not at the C terminus have been observed previously in brains of human patients with E200K familial CJD (10) or sporadic Creutzfeldt-Jakob disease (45)(46)(47). In contrast, PrP-res from patients with familial CJD associated with mutations such as P102L (11), F198S (12,13), and A117V (14, 15) is more often truncated at both the N and C termini.…”

Section: Discussionmentioning

confidence: 99%

“…Peptides derived from the amyloidogenic core of the 7-8-kDa PrP-res fragment present in patients with Gerstmann-Straü ssler-Scheinker syndrome (12)(13)(14)(15), are only toxic to neurons that express PrP (48,49). In contrast, a larger C-terminal, protease-resistant fragment associated with familial CJD (E200K mutation) (10) and similar to those described for sporadic Creutzfeldt-Jakob disease (45)(46)(47)) is toxic to neurons that do not express PrP (50). That different protease-resistant peptide fragments are associated with diseases with different clinical phenotypes raises the pos- FIG.…”

Section: Discussionmentioning

confidence: 99%

Flexible N-terminal Region of Prion Protein Influences Conformation of Protease-resistant Prion Protein Isoforms Associated with Cross-species Scrapie Infection in Vivo and in Vitro

Lawson¹,

Priola

Meade-White

et al. 2004

Journal of Biological Chemistry

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Transmissible spongiform encephalopathy (TSE) diseases are characterized by the accumulation in brain of an abnormal protease-resistant form of the host-encoded prion protein (PrP), PrP-res. PrP-res conformation differs among TSE agents derived from various sources, and these conformational differences are thought to influence the biological characteristics of these agents. In this study, we introduced deletions into the flexible N-terminal region of PrP (residues 34 -124) and investigated the effect of this region on the conformation of PrP-res generated in an in vitro cell-free conversion assay. PrP deleted from residues 34 to 99 generated 12-16-kDa protease-resistant bands with intact C termini but variable N termini. The variable N termini were the result of exposure of new protease cleavage sites in PrP-res between residues 130 and 157, suggesting that these new cleavage sites were caused by alterations in the conformation of the PrP-res generated. Similarly truncated 12-16-kDa PrP bands were also identified in brain homogenates from mice infected with mouse-passaged hamster scrapie as well as in the cellfree conversion assay using conditions that mimicked the hamster/mouse species barrier to infection. Thus, by its effects on PrP-res conformation, the flexible N-terminal region of PrP seemed to influence TSE pathogenesis and cross-species TSE transmission.

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“…While PrP C is fully hydrolyzed by PK, PrP Sc is recovered as PrP res , which consists of prion protein core fragments that are usually N-terminally cleaved by approximately 6 kDa. The exact extent of N-terminal cleavage is dependent on strain type-associated conformational conditions of PrP Sc (7,27,42,44,48). One of the major features of prion disease susceptibility and transmissibility is the PrP-related genetic variability of both host and donor, which, e.g., is evident in sheep (4).…”

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confidence: 99%

Proteinase K-Resistant Material in ARR/VRQ Sheep Brain Affected with Classical Scrapie Is Composed Mainly of VRQ Prion Protein

Jacobs

Bossers

Rézaei

et al. 2011

J Virol

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Classical scrapie is a prion disease in sheep and goats. In sheep, susceptibility to disease is genetically influenced by single amino acid substitutions. Genetic breeding programs aimed at enrichment of arginine-171 (171R) prion protein (PrP), the so-called ARR allele, in the sheep population have been demonstrated to be effective in reducing the occurrence of classical scrapie in the field. Understanding the molecular basis for this reduced prevalence would serve the assessment of ARR adaptation. The prion formation mechanism and conversion of PrP from the normal form (PrP C ) to the scrapie-associated form (PrP Sc ) could play a key role in this process. Therefore, we investigated whether the ARR allele substantially contributes to scrapie prion formation in naturally infected heterozygous 171Q/R animals. Two methods were applied to brain tissue of 171Q/R heterozygous sheep with natural scrapie to determine the relative amount of the 171R PrP fraction in PrP res , the proteinase K-resistant PrP Sc core. An antibody test differentiating between 171Q and 171R PrP fragments showed that PrP res was mostly composed of the 171Q allelotype. Furthermore, using a novel tool for prion research, endoproteinase Lys-C-digested PrP res yielded substantial amounts of a nonglycosylated and a monoglycosylated PrP fragment comprising codons 114 to 188. Following two-dimensional gel electrophoresis, only marginal amounts (<9%) of 171R PrP res were detected. Enhanced 171R res proteolytic susceptibility could be excluded. Thus, these data support a nearly zero contribution of 171R PrP in PrP res of 171R/Q field scrapie-infected animals. This is suggestive of a poor adaptation of classical scrapie to this resistance allele under these natural conditions.

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Intracerebral distribution of the abnormal isoform of the prion protein in sporadic Creutzfeldt-Jakob disease and fatal insomnia

Cited by 30 publications

References 57 publications

MRI Detection of the Cerebellar Syndrome in Creutzfeldt–Jakob Disease

MRI Detection of the Cerebellar Syndrome in Creutzfeldt–Jakob Disease

Flexible N-terminal Region of Prion Protein Influences Conformation of Protease-resistant Prion Protein Isoforms Associated with Cross-species Scrapie Infection in Vivo and in Vitro

Proteinase K-Resistant Material in ARR/VRQ Sheep Brain Affected with Classical Scrapie Is Composed Mainly of VRQ Prion Protein

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