Enhanced levels of scrapie responsive gene mRNA in BSE-infected mouse brain

Dandoy-Dron, Françoise; Benboudjema, Louisa; Guillo, Frédéric; Jaegly, Alexandre; Jasmin, C; Dormont, Dominique; Tovey, Michaël G.; Dron, Michel

doi:10.1016/s0169-328x(00)00028-0

Cited by 36 publications

(26 citation statements)

References 39 publications

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“…50 ALDC has been termed "scrapieresponsive protein 2 (scrg2)," and its mRNA is increased in scrapie infection. 51,52 We also confirmed an increase of ALDC in scrapie-infected mice using Western blot ( Figure 8) and immunohistochemical analyses (data not shown). In addition, we are first to report that ALDC is a new candidate citrullinated protein and that it was mainly expressed in reactive astrocytes of scrapie-infected brain.…”

Section: Discussionsupporting

confidence: 61%

Accumulation of Citrullinated Proteins by Up-Regulated Peptidylarginine Deiminase 2 in Brains of Scrapie-Infected Mice

Jang

Kim

Choi

et al. 2008

The American Journal of Pathology

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Peptidylarginine deiminases (PADs), which are a group of posttranslational modification enzymes, are involved in protein citrullination (deimination) by the conversion of peptidylarginine to peptidylcitrulline in a calcium concentration-dependent manner. Among the PADs, PAD2 is widely distributed in various tissues and is the only type that is expressed in brain. To elucidate the involvement of protein citrullination by PAD2 in the pathogenesis of brain-specific prion diseases, we examined the profiles of citrullinated proteins using the brains of scrapie-infected mice as a prion disease model. We found that, compared with controls, increased levels of citrullinated proteins of various molecular weights were detected in different brain sections of scrapie-infected mice. In support of this data, expression levels of PAD2 protein as well as its enzyme activity were significantly increased in brain sections of scrapie-infected mice, including hippocampus, brain stem, and striatum. Additionally, the expression levels of PAD2 mRNA were increased during scrapie infection. Moreover, PAD2 immunoreactivity was increased in scrapie-infected brains, with staining detected primarily in reactive astrocytes. Using two-dimensional electrophoresis and matrix-assisted laser desorption/ionization-time of flight mass spectrometry, various citrullinated proteins were identified in the brains of scrapie-infected mice, including glial fibrillary acidic protein, myelin basic protein, enolases, and aldolases. This study suggests that accumulated citrullinated proteins and abnormal activation of PAD2 may function in the pathogenesis of prion diseases and serve as potential therapeutic targets. Accumulation of misfolded proteins, posttranslational modification of proteins, alteration of free ion distribution, and perturbation of cellular redox homeostasis are general features of progressive neurodegenerative disorders. These changes have been observed consistently as part of the neuropathogenesis and neuropathology of prion diseases. Prion diseases are characterized by various neurological symptoms and common histopathological features such as spongiform degeneration of the central nervous system, reactive gliosis, neuronal loss, and, in some cases, formation of amyloid plaques. 1 It has been reported that all prion diseases are associated with the aberrant metabolism of prion protein (PrP). Conversion of the cellular prion protein (PrP C ) into an abnormal, protease-resistant and infectious isoform (PrP Sc ) is believed to be a principal molecular basis of prion diseases, 2 and the accumulation of PrP Sc in the central nervous system is thought to be responsible for neuronal loss and/or astrocytosis.

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Section: Discussionsupporting

confidence: 61%

Accumulation of Citrullinated Proteins by Up-Regulated Peptidylarginine Deiminase 2 in Brains of Scrapie-Infected Mice

Jang

Kim

Choi

et al. 2008

The American Journal of Pathology

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“…Complement C3d positive PrP deposits were often found associated with activated microglia in post mortem brain specimens of Creutzfeldt-Jakob disease (CJD) and Gerstmann-Sträussler-Scheinker disease (GSS) cases [48], and recent studies show that the C5b-9 complex (MAC) is localized on neurons in the brains of TSE patients [49]. Moreover, expression of C1q is increased in TSE affected brain areas in experimental mouse models of scrapie [52,53], suggesting a role for complement activation products in the pathogenesis of TSEs as well.…”

Section: Complement In Prion Diseasementioning

confidence: 99%

Amyloid Associated Proteins in Alzheimers and Prion Disease

Veerhuis

Rs²,

Familian³

2005

CDTCNSND

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Clustering of activated microglia in Abeta deposits is related to accumulation of amyloid associated factors and precedes the neurodegenerative changes in AD. Microglia-derived pro-inflammatory cytokines are suggested to be the driving force in AD pathology. Inflammation-related proteins, including complement factors, acute-phase proteins, pro-inflammatory cytokines, that normally are locally produced at low levels, are increasingly synthesized in Alzheimer's disease (AD) brain. Similar to AD, in prion diseases (Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease and experimentally scrapie infected mouse brain) amyloid associated factors and activated glial cells accumulate in amyloid deposits of conformational changed prion protein (PrPres). Biological properties of Abeta and prion (PrP) peptides, including their potential to activate microglia, relate to Abeta and PrP peptide fibrillogenic abilities that are influenced by certain amyloid associated factors. However, since small oligomers of amyloid forming peptides are more toxic to neurons than large fibrils, certain amyloid associated factors that enhance fibril formation, may sequester the potentially harmful Abeta and PrP peptides from the neuronal microenvironment. In this review the positive and negative actions of amyloid associated factors on amyloid peptide fibril formation and on the fibrillation state related activation of microglia will be discussed. Insight in these mechanisms will enable the design of specific therapies to prevent neurodegenerative diseases in which amyloid accumulation and glial activation are prominent early features.

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“…This gene was up-regulated in brains of scrapie prion-and BSE-infected mice and in brains of patients with sporadic CJD (Dandoy- Dron et al, 2000;Dandoy-Dron et al, 1998;Dron et al, 1998). In the CNS of prion-infected mice up-regulated Scrg1 was associated with autophagic vacuoles which were observed at the terminal stage of disease (Dron et al, 2005).…”

Section: Autophagy and Prion Infectionmentioning

confidence: 99%

Autophagy, Prion Infection and their Mutual Interactions

Heiseke

Aguib²,

Schätzl³

2010

Current Issues in Molecular Biology

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Prion diseases are infectious and fatal neurodegenerative disorders of man and animals which are characterized by spongiform degeneration in the central nervous system. Prion propagation involves the endocytic pathway and endosomal and lysosomal compartments are implicated in trafficking and re-cycling as well as final degradation of prions. Shifting the equilibrium between propagation and lysosomal clearance to the latter impairs cellular prion load. This and earlier findings of autophagic vacuoles in correlation to prion infections both in in vitro and in vivo studies prompted us and others to analyze the role of autophagy in prion infection. Autophagy is a fundamental cellular bulk degradation process for e.g. organelles or cytoplasmic proteins which has many implications for physiology and patho-physiology of cells and whole organisms. In various neurodegenerative disease models mainly protective functions of autophagy were recently described. In this review, we focus on recent findings which correlate autophagy and its manipulations with prion infection scenarios, and discuss perspectives and future directions. The findings summarized here add to the knowledge of the role of autophagy in neurodegeneration and provide interesting new insight into how non-cytosolic aggregated proteins might be subjected to autophagic clearance.

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Enhanced levels of scrapie responsive gene mRNA in BSE-infected mouse brain

Cited by 36 publications

References 39 publications

Accumulation of Citrullinated Proteins by Up-Regulated Peptidylarginine Deiminase 2 in Brains of Scrapie-Infected Mice

Accumulation of Citrullinated Proteins by Up-Regulated Peptidylarginine Deiminase 2 in Brains of Scrapie-Infected Mice

Amyloid Associated Proteins in Alzheimers and Prion Disease

Autophagy, Prion Infection and their Mutual Interactions

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