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    Preserving prion strain identity upon replication of prions in vitro using recombinant prion protein

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    Author
    Makarava, N.
    Savtchenko, R.
    Lasch, P.
    Date
    2018
    Journal
    Acta neuropathologica communications
    Publisher
    BMC
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://dx.doi.org/10.1186/s40478-018-0597-y
    Abstract
    Last decade witnessed an enormous progress in generating authentic infectious prions or PrPSc in vitro using recombinant prion protein (rPrP). Previous work established that rPrP that lacks posttranslational modification is able to support replication of highly infectious PrPSc with assistance of cofactors of polyanionic nature and/or lipids. Unexpectedly, previous studies also revealed that seeding of rPrP by brain-derived PrPSc gave rise to new prion strains with new disease phenotypes documenting loss of a strain identity upon replication in rPrP substrate. Up to now, it remains unclear whether prion strain identity can be preserved upon replication in rPrP. The current study reports that faithful replication of hamster strain SSLOW could be achieved in vitro using rPrP as a substrate. We found that a mixture of phosphatidylethanolamine (PE) and synthetic nucleic acid polyA was sufficient for stable replication of hamster brain-derived SSLOW PrPSc in serial Protein Misfolding Cyclic Amplification (sPMCA) that uses hamster rPrP as a substrate. The disease phenotype generated in hamsters upon transmission of recombinant PrPSc produced in vitro was strikingly similar to the original SSLOW diseases phenotype with respect to the incubation time to disease, as well as clinical, neuropathological and biochemical features. Infrared microspectroscopy (IR-MSP) indicated that PrPSc produced in animals upon transmission of recombinant PrPSc is structurally similar if not identical to the original SSLOW PrPSc. The current study is the first to demonstrate that rPrP can support replication of brain-derived PrPSc while preserving its strain identity. In addition, the current work is the first to document that successful propagation of a hamster strain could be achieved in vitro using hamster rPrP.
    Keyword
    Prion diseases
    Prion strain
    Prions
    Recombinant prion protein
    Replication cofactors
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85062022587&doi=10.1186%2fs40478-018-0597-y&partnerID=40&md5=2bf4c1377f7124915290dca591d57bb9; http://hdl.handle.net/10713/9058
    ae974a485f413a2113503eed53cd6c53
    10.1186/s40478-018-0597-y
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      Correction to: preserving prion strain identity upon replication of prions in vitro using recombinant prion protein (Acta neuropathologica communications (2018) 6 1 (92))

      Makarava, N.; Savtchenko, R.; Lasch, P. (BMC, 2018)
      Figure 6 of the original publication [1] contained an error in the Wavenumber in panels B and C. The wavenumbers 1616 (Cm-1) in panels B and C should have been 1516 (cm-1). The updated figure has been published in this correction article; the original article has been updated.
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      Region-specific sialylation pattern of prion strains provides novel insight into prion neurotropism

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      Region-specific glial homeostatic signature in prion diseases is replaced by a uniform neuroinflammation signature, common for brain regions and prion strains with different cell tropism

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      Chronic neuroinflammation is recognized as a major neuropathological hallmark in a broad spectrum of neurodegenerative diseases including Alzheimer's, Parkinson's, Frontal Temporal Dementia, Amyotrophic Lateral Sclerosis, and prion diseases. Both microglia and astrocytes exhibit region-specific homeostatic transcriptional identities, which under chronic neurodegeneration, transform into reactive phenotypes in a region- and disease-specific manner. Little is known about region-specific identity of glia in prion diseases. The current study was designed to determine whether the region-specific homeostatic signature of glia changes with the progression of prion diseases, and whether these changes occur in a region-dependent or universal manner. Also of interest was whether different prion strains give rise to different reactive phenotypes. To answer these questions, we analyzed gene expression in the thalamus, cortex, hypothalamus and hippocampus of mice infected with 22L and ME7 prion strains using a Nanostring Neuroinflammation panel at the subclinical, early clinical and advanced stages of the disease. We found that at the preclinical stage of the disease, the region-specific homeostatic identities were preserved. However, with the appearance of clinical signs, the region-specific signatures were partially lost and replaced with a neuroinflammation signature. While the same sets of genes were activated by both prion strains, the timing of neuroinflammation and the degree of activation in different brain regions was strain-specific. Changes in astrocyte function scored at the top of the activated pathways. Moreover, clustering analysis suggested that the astrocyte function pathway responded to prion infection prior to the Activated Microglia or Neuron and Neurotransmission pathways. The current work established neuroinflammation gene expression signature associated with prion diseases. Our results illustrate that with the disease progression, the region-specific homeostatic transcriptome signatures are replaced by the region-independent neuroinflammation signature, which is common for prion strains with different cell tropism. The prion-associated neuroinflammation signature identified in the current study overlapped only partially with the microglia degenerative phenotype and the disease-associated microglia phenotype reported for animal models of other neurodegenerative diseases. Copyright 2020 The Authors
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