Distinct patterns of spread of prion infection in brains of mice expressing anchorless or anchored forms of prion protein

Rangel, Alejandra; Race, Brent; Phillips, Katie; Striebel, James F.; Kurtz, Nancy; Chesebro, Bruce

doi:10.1186/2051-5960-2-8

Cited by 28 publications

(30 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Additionally, others have reported that deletion of Ccl2 (20) or Cxcr3 (the receptor for CXCL10, CXCL9, and CXCL11, which are increased in our model) (46) can increase survival time in mice after scrapie infection, suggesting that signaling through these chemokines and their receptors can lead to damage. IL-1Ra has more recently been demonstrated to increase JNK phosphorylation in hippocampal synaptosomes (36), potentially contributing to neurodegeneration (23). Furthermore, a persistent inflammatory environment, similar to that observed in prion disease, with increased expression of cytokines has been shown to direct neuronal precursor cells to differentiate into astroglia, reducing the percentage of new neurons and leading to an excess of astroglia (10,16,40).…”

Section: Discussionmentioning

confidence: 99%

“…For PrPres immunoblotting, tissue samples were analyzed as described previously (3,35). Briefly, 0.36 mg of whole-brain equivalent was treated with proteinase K, separated by SDS-PAGE, transferred to a polyvinylidene difluoride membrane, and probed with a 1:100 dilution of monoclonal human anti-PrP antibody D13 derived from cell culture supernatants produced in our laboratory from CHO cells expressing the D13 antibody construct (36). The secondary antibody was peroxidase-conjugated anti-human IgG, used at 1:10,000 (Sigma), and immunoreactive bands were visualized using an enhanced chemiluminescence (ECL) detection system (GE Healthcare).…”

Section: Methodsmentioning

confidence: 99%

“…For the detection of microglia, sections were probed with antibodies at 1:2,000 against ionized calcium-binding adapter-1 (IBA-1), and for astrocytes, sections were probed with antibodies at 1:3,500 against glial fibrillary acidic protein (GFAP). Antigen retrieval, primary and secondary antibody probings, and detection were carried out as previously described (36).…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Prion Infection of Mouse Brain Reveals Multiple New Upregulated Genes Involved in Neuroinflammation or Signal Transduction

Carroll

Striebel

Race

et al. 2015

J Virol

Self Cite

View full text Add to dashboard Cite

Gliosis is often a preclinical pathological finding in neurodegenerative diseases, including prion diseases, but the mechanisms facilitating gliosis and neuronal damage in these diseases are not understood. To expand our knowledge of the neuroinflammatory response in prion diseases, we assessed the expression of key genes and proteins involved in the inflammatory response and signal transduction in mouse brain at various times after scrapie infection. In brains of scrapie-infected mice at pre-and postclinical stages, we identified 15 previously unreported differentially expressed genes related to inflammation or activation of the STAT signal transduction pathway. Levels for the majority of differentially expressed genes increased with time postinfection. In quantitative immunoblotting experiments of STAT proteins, STAT1␣, phosphorylated-STAT1␣ (pSTAT1␣), and pSTAT3 were increased between 94 and 131 days postinfection (p.i.) in brains of mice infected with strain 22L. Furthermore, a select group of STAT-associated genes was increased preclinically during scrapie infection, suggesting early activation of the STAT signal transduction pathway. Comparison of inflammatory markers between mice infected with scrapie strains 22L and RML indicated that the inflammatory responses and gene expression profiles in the brains were strikingly similar, even though these scrapie strains infect different brain regions. The endogenous interleukin-1 receptor antagonist (IL-1Ra), an inflammatory marker, was newly identified as increasing preclinically in our model and therefore might influence scrapie pathogenesis in vivo. However, in IL1Ra-deficient or overexpressor transgenic mice inoculated with scrapie, neither loss nor overexpression of IL-1Ra demonstrated any observable effect on gliosis, protease-resistant prion protein (PrPres) formation, disease tempo, pathology, or expression of the inflammatory genes analyzed. IMPORTANCEPrion infection leads to PrPres deposition, gliosis, and neuroinflammation in the central nervous system before signs of clinical illness. Using a scrapie mouse model of prion disease to assess various time points postinoculation, we identified 15 unreported genes that were increased in the brains of scrapie-infected mice and were associated with inflammation and/or JAK-STAT activation. Comparison of mice infected with two scrapie strains (22L and RML), which have dissimilar neuropathologies, indicated that the inflammatory responses and gene expression profiles in the brains were similar. Genes that increased prior to clinical signs might be involved in controlling scrapie infection or in facilitating damage to host tissues. We tested the possible role of the endogenous IL-1Ra, which was increased at 70 days p.i. In scrapie-infected mice deficient in or overexpressing IL-1Ra, there was no observable effect on gliosis, PrPres formation, disease tempo, pathology, or expression of inflammatory genes analyzed. P rion diseases are infectious progressive neurodegenerative disorders that can affect both h...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Prion Infection of Mouse Brain Reveals Multiple New Upregulated Genes Involved in Neuroinflammation or Signal Transduction

Carroll

Striebel

Race

et al. 2015

J Virol

Self Cite

View full text Add to dashboard Cite

show abstract

“…Addition of a glycosylphosphatidylinositol (GPI) anchor to PrP is another type of posttranslational modification which is known to affect PrPres formation and deposition (36,37). The presence or absence of GPI anchoring of PrP has also been shown to influence scrapie strain-specific properties in vitro (38).…”

mentioning

confidence: 99%

Increased Infectivity of Anchorless Mouse Scrapie Prions in Transgenic Mice Overexpressing Human Prion Protein

Race

Phillips

Meade-White

et al. 2015

J Virol

Self Cite

View full text Add to dashboard Cite

Prion protein (PrP) is found in all mammals, mostly as a glycoprotein anchored to the plasma membrane by a C-terminal glycosylphosphatidylinositol (GPI) linkage. Following prion infection, host protease-sensitive prion protein (PrPsen or PrPC) is converted into an abnormal, disease-associated, protease-resistant form (PrPres). Biochemical characteristics, such as the PrP amino acid sequence, and posttranslational modifications, such as glycosylation and GPI anchoring, can affect the transmissibility of prions as well as the biochemical properties of the PrPres generated. Previous in vivo studies on the effects of GPI anchoring on prion infectivity have not examined cross-species transmission. In this study, we tested the effect of lack of GPI anchoring on a species barrier model using mice expressing human PrP. In this model, anchorless 22L prions derived from tg44 mice were more infectious than 22L prions derived from C57BL/10 mice when tested in tg66 transgenic mice, which expressed wild-type anchored human PrP at 8-to 16-fold above normal. Thus, the lack of the GPI anchor on the PrPres from tg44 mice appeared to reduce the effect of the mouse-human PrP species barrier. In contrast, neither source of prions induced disease in tgRM transgenic mice, which expressed human PrP at 2-to 4-fold above normal. IMPORTANCE Prion protein (PrP) is found in all mammals, usually attached to cells by an anchor molecule called GPI. Following prion infection, PrP is converted into a disease-associated form (PrPres). While most prion diseases are species specific, this finding is not consistent, and species barriers differ in strength. The amino acid sequence of PrP varies among species, and this variability affects prion species barriers. However, other PrP modifications, including glycosylation and GPI anchoring, may also influence cross-species infectivity. We studied the effect of PrP GPI anchoring using a mouse-to-human species barrier model. Experiments showed that prions produced by mice expressing only anchorless PrP were more infectious than prions produced in mice expressing anchored PrP. Thus, the lack of the GPI anchor on prions reduced the effect of the mouse-human species barrier. Our results suggest that prion diseases that produce higher levels of anchorless PrP may pose an increased risk for cross-species infection. P rion diseases, also known as transmissible spongiform encephalopathies (TSEs), are fatal neurodegenerative diseases that occur in many mammals, including humans. Central to all prion diseases is the conversion of the normal host prion protein (PrPsen or PrPC) into an abnormal, protease-resistant form (PrPres) associated with disease. In previous studies, PrPres and infectivity were generated concurrently in a cell-free in vitro system, proving that live cells were not required for formation of new prion infectivity in a cell-free in vitro system (1-4), a finding which supported the role of PrPres as the infectious prion agent (5). During the course of prion disease, repeated conversion of P...

show abstract

“…Slight variations in regional PrP Sc deposition between infected mice is typical. Immunohistochemical and immunoblot analyses were performed as described previously (Striebel et al, 2011;Rangel et al, 2014).…”

mentioning

confidence: 99%

Knockout of fractalkine receptor Cx3cr1 does not alter disease or microglial activation in prion-infected mice

Striebel

Race

Carroll

et al. 2016

Journal of General Virology

Self Cite

View full text Add to dashboard Cite

Distinct patterns of spread of prion infection in brains of mice expressing anchorless or anchored forms of prion protein

Cited by 28 publications

References 46 publications

Prion Infection of Mouse Brain Reveals Multiple New Upregulated Genes Involved in Neuroinflammation or Signal Transduction

Prion Infection of Mouse Brain Reveals Multiple New Upregulated Genes Involved in Neuroinflammation or Signal Transduction

Increased Infectivity of Anchorless Mouse Scrapie Prions in Transgenic Mice Overexpressing Human Prion Protein

Knockout of fractalkine receptor Cx3cr1 does not alter disease or microglial activation in prion-infected mice

Contact Info

Product

Resources

About