Disease phenotype in sheep after infection with cloned murine scrapie strains

Sisó, Sílvia; Chianini, Francesca; Eaton, Samantha L.; Witz, Janey; Hamilton, Scott L.; Martin, Stuart; Finlayson, J.; Pang, Yvonne; Stewart, Paula; Steele, Philip; Dagleish, Mark P.; Goldmann, Wilfred; Reid, H.W.; Jeffrey, Martin; González, Lorenzo

doi:10.4161/pri.18990

Cited by 12 publications

(21 citation statements)

References 36 publications

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“…Other works previously found a similar possible association of 22L PrPSc with hippocampal astroglia at 56 dpi, but data on other brain regions was not reported [ 46 ]. In contrast to strain 22L, strain ME7 PrPSc almost never localized with astroglia, microglia or oligodendroglia, but instead associated primarily with neurons and neuropil, similar to what was previously reported at clinical times by others [ 12 , 15 ].…”

Section: Discussionsupporting

confidence: 88%

Prion Strain Differences in Accumulation of PrPSc on Neurons and Glia Are Associated with Similar Expression Profiles of Neuroinflammatory Genes: Comparison of Three Prion Strains

et al. 2016

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Misfolding and aggregation of host proteins are important features of the pathogenesis of neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia and prion diseases. In all these diseases, the misfolded protein increases in amount by a mechanism involving seeded polymerization. In prion diseases, host prion protein is misfolded to form a pathogenic protease-resistant form, PrPSc, which accumulates in neurons, astroglia and microglia in the CNS. Here using dual-staining immunohistochemistry, we compared the cell specificity of PrPSc accumulation at early preclinical times post-infection using three mouse scrapie strains that differ in brain regional pathology. PrPSc from each strain had a different pattern of cell specificity. Strain 22L was mainly associated with astroglia, whereas strain ME7 was mainly associated with neurons and neuropil. In thalamus and cortex, strain RML was similar to 22L, but in substantia nigra, RML was similar to ME7. Expression of 90 genes involved in neuroinflammation was studied quantitatively using mRNA from thalamus at preclinical times. Surprisingly, despite the cellular differences in PrPSc accumulation, the pattern of upregulated genes was similar for all three strains, and the small differences observed correlated with variations in the early disease tempo. Gene upregulation correlated with activation of both astroglia and microglia detected in early disease prior to vacuolar pathology or clinical signs. Interestingly, the profile of upregulated genes in scrapie differed markedly from that seen in two acute viral CNS diseases (LaCrosse virus and BE polytropic Friend retrovirus) that had reactive gliosis at levels similar to our prion-infected mice.

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Section: Discussionsupporting

confidence: 88%

Prion Strain Differences in Accumulation of PrPSc on Neurons and Glia Are Associated with Similar Expression Profiles of Neuroinflammatory Genes: Comparison of Three Prion Strains

et al. 2016

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“…In addition, the formation of PrP Sc molecular characteristics occurs at the very early stage, as the glycosylation patterns of PrP Sc are the same among the brain samples collected at the early, mid and terminal terms during infection with the 1st passage of ME7-ha and 139A-ha (9). In another study of ours on protein misfolding cyclic amplification (PMCA) (Gao et al, unpublished data), we illustrate that mouseadapted agent 139A can efficiently induce the formation of PK-resistant PrP (PrP res ) when using hamster brain and muscle homogenates as the substrates, accompanied by the same shift in PrP res glycosylation patterns as in the interspecies infection in vivo (19). Of note, such a shift in PrP res glycosylation patterns is observed in the 1st round of PMCA and stably maintained in the subsequent rounds.…”

Section: Discussionsupporting

confidence: 50%

Successive passaging of the scrapie strains, ME7-ha and 139A-ha, generated by the interspecies transmission of mouse-adapted strains into hamsters markedly shortens the incubation times, but maintains their molecular and pathological properties

Shi

Xiao

Zhang

et al. 2015

International Journal of Molecular Medicine

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As a type of zoonotic disease, prion diseases may be transmitted naturally and experimentally among species. In a previous study, we demonstrated that the mouse-adapted scrapie strains, ME7 (ME7-mo) and 139A (139A-mo), can overcome the species barrier and induce experimental scrapie when inoculated into Golden hamsters and generated 2 new hamster-adapted strains, ME7 (ME7-ha) and 139A (139A-ha). In the present study, in order to assess the infectivity and other molecular and neuropathological properties of the newly formed scrapie agents, ME7-ha and 139A-ha were further intracerebrally inoculated into hamsters. Compared with infection with 1st passage strains, the incubation times and clinical courses of infection with 2nd passage strains were markedly shorter, which were quite comparable with those of the mice infected with their parent mouse strains. The glycosylation patterns of brain PrP(Sc) in the animals infected with the 2nd passage of those 2 strains maintained similar features as those in the animals infected with the 1st passage of those strains, with predominantly diglycosylated PrP(Sc). Neuropathological assays revealed comparable spongiform degeneration and microglia proliferation in the brain tissues from the infected mice and hamsters, but markedly more plaque-like deposits of PrP(Sc) and more severe astrogliosis in the brains of the hamster. These data indicate that the strains, ME7-ha 1st and 139A-ha 1st generated by interspecies infection can passage in the new host hamster and stably maintain their molecular and neuropathological characteristics.

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“…Another key issue is the involvement of astroglial cells in prion replication, and propagation to neighboring cells (i.e., neurons) and throughout the CNS, which has been proposed to occur in prion diseases [ 34 , 61 ] and other neurodegenerative disorders associated with prion-like proteins [ 62 ]. While the direct participation of astrocytes and neurons in PrP Sc replication and spread is well recognized [ 43 , 63 , 64 , 65 , 66 , 67 , 68 , 69 ], the role of microglia in such processes is still debated [ 34 ]. The low basal levels of PrP C in microglia may suggest that these cells unlikely support the PrP C -to-PrP Sc transition and act as foci of prion propagation.…”

Section: Microglia Function In Health and Prion Diseasesmentioning

confidence: 99%

Microglia in Prion Diseases: Angels or Demons?

Peggion

Stella

Lorenzon

et al. 2020

IJMS

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Prion diseases are rare transmissible neurodegenerative disorders caused by the accumulation of a misfolded isoform (PrPSc) of the cellular prion protein (PrPC) in the central nervous system (CNS). Neuropathological hallmarks of prion diseases are neuronal loss, astrogliosis, and enhanced microglial proliferation and activation. As immune cells of the CNS, microglia participate both in the maintenance of the normal brain physiology and in driving the neuroinflammatory response to acute or chronic (e.g., neurodegenerative disorders) insults. Microglia involvement in prion diseases, however, is far from being clearly understood. During this review, we summarize and discuss controversial findings, both in patient and animal models, suggesting a neuroprotective role of microglia in prion disease pathogenesis and progression, or—conversely—a microglia-mediated exacerbation of neurotoxicity in later stages of disease. We also will consider the active participation of PrPC in microglial functions, by discussing previous reports, but also by presenting unpublished results that support a role for PrPC in cytokine secretion by activated primary microglia.

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Disease phenotype in sheep after infection with cloned murine scrapie strains

Cited by 12 publications

References 36 publications

Prion Strain Differences in Accumulation of PrPSc on Neurons and Glia Are Associated with Similar Expression Profiles of Neuroinflammatory Genes: Comparison of Three Prion Strains

Prion Strain Differences in Accumulation of PrPSc on Neurons and Glia Are Associated with Similar Expression Profiles of Neuroinflammatory Genes: Comparison of Three Prion Strains

Successive passaging of the scrapie strains, ME7-ha and 139A-ha, generated by the interspecies transmission of mouse-adapted strains into hamsters markedly shortens the incubation times, but maintains their molecular and pathological properties

Microglia in Prion Diseases: Angels or Demons?

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