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Publication Detail
In vitro screen of prion disease susceptibility genes using the scrapie cell assay.
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Journal Article
  • Authors:
    Brown CA, Schmidt C, Poulter M, Hummerich H, Klöhn P-C, Jat P, Mead S, Collinge J, Lloyd SE
  • Publication date:
    01/10/2014
  • Pagination:
    5102, 5108
  • Journal:
    Hum Mol Genet
  • Volume:
    23
  • Issue:
    19
  • Status:
    Published
  • Country:
    England
  • PII:
    hmg/ddu233
  • Language:
    eng
  • Keywords:
    Animals, Cell Line, Gene Expression, Gene Knockout Techniques, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, In Vitro Techniques, Mice, Prion Diseases, Quantitative Trait Loci, RNA Interference, Scrapie
Abstract
Prion diseases (transmissible spongiform encephalopathies) are fatal neurodegenerative diseases, including Creutzfeldt-Jakob disease in humans, scrapie in sheep and bovine spongiform encephalopathy in cattle. While genome-wide association studies in human and quantitative trait loci mapping in mice have provided evidence for multiple susceptibility genes, few of these have been confirmed functionally. Phenotyping mouse models is generally the method of choice. However, this is not a feasible option where many novel genes, without pre-existing models, would need to be tested. We have therefore developed and applied an in-vitro screen to triage and prioritize candidate modifier genes for more detailed future studies which is faster, far more cost effective and ethical relative to mouse bioassay models. An in vitro prion bioassay, the scrapie cell assay, uses a neuroblastoma-derived cell line (PK1) that is susceptible to RML prions and able to propagate prions at high levels. In this study, we have generated stable gene silencing and/or overexpressing PK1-derived cell lines to test whether perturbation of 14 candidate genes affects prion susceptibility. While no consistent differences were determined for seven genes, highly significant changes were detected for Zbtb38, Sorcs1, Stmn2, Hspa13, Fkbp9, Actr10 and Plg, suggesting that they play key roles in the fundamental processes of prion propagation or clearance. Many neurodegenerative diseases involve the accumulation of misfolded protein aggregates and 'prion-like' seeding and spread has been implicated in their pathogenesis. It is therefore expected that some of these prion-modifier genes may be of wider relevance in neurodegeneration.
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MRC Prion Unit at UCL
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MRC Prion Unit at UCL
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MRC Prion Unit at UCL
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MRC Prion Unit at UCL
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