Distinctive cerebellar immunoreactivity for the prion protein in familial (E200K) Creutzfeldt-Jakob disease

Jarius, Christa; Kovács, Gábor G.; Belay, Girma; Hainfellner, Johannes A.; Mitrová, E; Budka, Herbert

doi:10.1007/s00401-002-0664-z

Cited by 25 publications

(6 citation statements)

References 21 publications

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“…The present anatomical analysis provides evidence that both scrapie PrP 22L and PrP ME7 precipitate according to a parasagittal banding pattern in the mouse cerebellum, as previously documented , while the 6PB1 bovine strain displays a random accumulation pattern. Although there is substantial evidence that prions spread to the cerebellar cortex along well defined, synaptically linked neural pathways , we here show that the neuroinvasion route does not however impact on the banding patterns of PrP scrapie deposits.…”

Section: Discussionsupporting

confidence: 85%

Cerebellar compartmentation of prion pathogenesis

et al. 2017

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In prion diseases, the brain lesion profile is influenced by the prion "strain" properties, the invasion route to the brain, and still unknown host cell-specific parameters. To gain insight into those endogenous factors, we analyzed the histopathological alterations induced by distinct prion strains in the mouse cerebellum. We show that 22L and ME7 scrapie prion proteins (PrP , PrP ), but not bovine spongiform encephalopathy PrP , accumulate in a reproducible parasagittal banding pattern in the cerebellar cortex of infected mice. Such banding pattern of PrP aggregation did not depend on the neuroinvasion route, but coincided with the parasagittal compartmentation of the cerebellum mostly defined by the expression of zebrins, such as aldolase C and the excitatory amino acid transporter 4, in Purkinje cells. We provide evidence that Purkinje cells display a differential, subtype-specific vulnerability to 22L prions with zebrin-expressing Purkinje cells being more resistant to prion toxicity, while in stripes where PrP accumulated most zebrin-deficient Purkinje cells are lost and spongiosis accentuated. In addition, in PrP stripes, enhanced reactive astrocyte processes associated with microglia activation support interdependent events between the topographic pattern of Purkinje cell death, reactive gliosis and PrP accumulation. Finally, we find that in preclinically-ill mice prion infection promotes at the membrane of astrocytes enveloping Purkinje cell excitatory synapses, upregulation of tumor necrosis factor-α receptor type 1 (TNFR1), a key mediator of the neuroinflammation process. These overall data show that Purkinje cell sensitivity to prion insult is locally restricted by the parasagittal compartmentation of the cerebellum, and that perisynaptic astrocytes may contribute to prion pathogenesis through prion-induced TNFR1 upregulation.

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Section: Discussionsupporting

confidence: 85%

Cerebellar compartmentation of prion pathogenesis

et al. 2017

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“…Our patient did not develop myoclous or EEG PSWCs, which are very common in published E200K-129M cases (myoclonus in 73% and PSWCs in 75%) [33,34]. A characteristic stripe-like pattern with a perpendicular orientation of PrP Sc deposits in the cerebellum noted in published E200K-129M [14,26,35] cases was not observed in our case. In addition, our patient had type 2 PrP Sc , whereas E200K-129M cases have type 1, 2 or mixture of both types [14,29,36].…”

Section: Discussionsupporting

confidence: 49%

Genetic CJD with a novel E200G mutation in the prion protein gene and comparison with E200K mutation cases

Kim

Calì

Oehler³

et al. 2013

acta neuropathol commun

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A novel point mutation resulting in a glutamate-to-glycine substitution in PRNP at codon 200, E200G with codon 129 MV polymorphism (cis valine) and type 2 PrPSc was identified in a patient with a prolonged disease course leading to pathology-proven Jakob-Creutzfeldt disease. Despite the same codon as the most common genetic form of human PRNP mutation, E200K, this novel mutation (E200G) presented with a different clinical and pathological phenotype, including prolonged duration, large vacuoles, no vacuolation in the hippocampus, severe neuronal loss in the thalamus, mild cerebellar involvement, and abundant punctate linear and curvilinear deposition of PrPSc in synaptic boutons and axonal terminals along the dendrites.

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“…A patch‐like distribution of PrP Sc has been found in the cerebellum of familial CJD linked to a 144‐base‐pair insertion within the PrP gene, suggesting a topographic pattern [30]. In addition, in familial cases linked to an E200K mutation, areas of PrP Sc immunoreactivity were located in the ML in a stripe‐like distribution perpendicular to the pial surface resembling the arborization of the climbing fibres [31]. Hence, the spatial patterns of the surviving Purkinje cells and the pathological changes in the ML are consistent with a topographic pattern to the degeneration of the cerebellum.…”

Section: Discussionmentioning

confidence: 97%

A quantitative study of the pathological changes in the cerebellum in 15 cases of variant Creutzfeldt–Jakob disease (vCJD)

Armstrong¹,

Ironside²,

Cairns³

2009

Neuropathology Appl Neurobio

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Aims: To determine in the cerebellum in variant Creutzfeldt-Jakob disease (vCJD): (i) whether the pathology affected all laminae; (ii) the spatial topography of the pathology along the folia; (iii) spatial correlations between the pathological changes; and (iv) whether the pathology was similar to that of the common methionine/methionine Type 1 subtype of sporadic CJD. Methods: Sequential cerebellar sections of 15 cases of vCJD were stained with haematoxylin and eosin, or immunolabelled with monoclonal antibody 12F10 against prion protein (PrP) and studied using spatial pattern analysis. Results: Loss of Purkinje cells was evident compared with control cases. Densities of the vacuolation and the protease-resistant form of prion protein (PrP Sc ) (diffuse and florid plaques) were greater in the granule cell layer (GL) than the molecular layer (ML). In the ML, vacuoles and PrP Sc plaques occurred in clusters regularly distributed along the folia with larger clusters of vacuoles and diffuse plaques in the GL. There was a negative spatial correlation between the vacuoles and the surviving Purkinje cells in the ML. There was a positive spatial correlation between the vacuoles and diffuse PrP Sc plaques in the ML and GL. Conclusions: (i) all laminae were affected by the pathology, the GL more severely than the ML; (ii) the pathology was topographically distributed along the folia especially in the Purkinje cell layer and ML; (iii) pathological spread may occur in relation to the loop of anatomical connections involving the cerebellum, thalamus, cerebral cortex and pons; and (iv) there were pathological differences compared with methionine/methionine Type 1 sporadic CJD.

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Distinctive cerebellar immunoreactivity for the prion protein in familial (E200K) Creutzfeldt-Jakob disease

Cited by 25 publications

References 21 publications

Cerebellar compartmentation of prion pathogenesis

Cerebellar compartmentation of prion pathogenesis

Genetic CJD with a novel E200G mutation in the prion protein gene and comparison with E200K mutation cases

A quantitative study of the pathological changes in the cerebellum in 15 cases of variant Creutzfeldt–Jakob disease (vCJD)

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