Pelagia Deriziotis

Publications (7)102.88 Total impact

• Article: Neurogenomics of speech and language disorders: the road ahead.

  Pelagia Deriziotis, Simon E Fisher
  [show abstract] [hide abstract]
  ABSTRACT: Next-generation sequencing is set to transform the discovery of genes underlying neurodevelopmental disorders, and so offer important insights into the biological bases of spoken language. Success will depend on functional assessments in neuronal cell lines, animal models and humans themselves.
  Genome biology 04/2013; 14(4):204. · 6.63 Impact Factor
• Source

  Available from: David Smith

  Article: Misfolded PrP impairs the UPS by interaction with the 20S proteasome and inhibition of substrate entry

  Pelagia Deriziotis, Ralph Andr|[eacute, David M Smith, Rob Goold, Kerri J Kinghorn, Mark Kristiansen, James A Nathan, Rina Rosenzweig, Dasha Krutauz, Michael H Glickman, John Collinge, Alfred L Goldberg, Sarah J Tabrizi
  [show abstract] [hide abstract]
  ABSTRACT: Prion diseases are associated with the conversion of cellular prion protein (PrP
  The EMBO Journal 07/2011; 30(15):3065-3077. · 9.20 Impact Factor
• Article: Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations.

  Brian J O'Roak, Pelagia Deriziotis, Choli Lee, Laura Vives, Jerrod J Schwartz, Santhosh Girirajan, Emre Karakoc, Alexandra P Mackenzie, Sarah B Ng, Carl Baker, Mark J Rieder, Deborah A Nickerson, Raphael Bernier, Simon E Fisher, Jay Shendure, Evan E Eichler
  [show abstract] [hide abstract]
  ABSTRACT: Evidence for the etiology of autism spectrum disorders (ASDs) has consistently pointed to a strong genetic component complicated by substantial locus heterogeneity. We sequenced the exomes of 20 individuals with sporadic ASD (cases) and their parents, reasoning that these families would be enriched for de novo mutations of major effect. We identified 21 de novo mutations, 11 of which were protein altering. Protein-altering mutations were significantly enriched for changes at highly conserved residues. We identified potentially causative de novo events in 4 out of 20 probands, particularly among more severely affected individuals, in FOXP1, GRIN2B, SCN1A and LAMC3. In the FOXP1 mutation carrier, we also observed a rare inherited CNTNAP2 missense variant, and we provide functional support for a multi-hit model for disease risk. Our results show that trio-based exome sequencing is a powerful approach for identifying new candidate genes for ASDs and suggest that de novo mutations may contribute substantially to the genetic etiology of ASDs.
  Nature Genetics 06/2011; 43(6):585-9. · 35.53 Impact Factor
• Article: Misfolded PrP impairs the UPS by interaction with the 20S proteasome and inhibition of substrate entry.

  Pelagia Deriziotis, Ralph André, David M Smith, Rob Goold, Kerri J Kinghorn, Mark Kristiansen, James A Nathan, Rina Rosenzweig, Dasha Krutauz, Michael H Glickman, John Collinge, Alfred L Goldberg, Sarah J Tabrizi
  [show abstract] [hide abstract]
  ABSTRACT: Prion diseases are associated with the conversion of cellular prion protein (PrP(C)) to toxic β-sheet isoforms (PrP(Sc)), which are reported to inhibit the ubiquitin-proteasome system (UPS). Accordingly, UPS substrates accumulate in prion-infected mouse brains, suggesting impairment of the 26S proteasome. A direct interaction between its 20S core particle and PrP isoforms was demonstrated by immunoprecipitation. β-PrP aggregates associated with the 20S particle, but did not impede binding of the PA26 complex, suggesting that the aggregates do not bind to its ends. Aggregated β-PrP reduced the 20S proteasome's basal peptidase activity, and the enhanced activity induced by C-terminal peptides from the 19S ATPases or by the 19S regulator itself, including when stimulated by polyubiquitin conjugates. However, the 20S proteasome was not inhibited when the gate in the α-ring was open due to a truncation mutation or by association with PA26/PA28. These PrP aggregates inhibit by stabilising the closed conformation of the substrate entry channel. A similar inhibition of substrate entry into the proteasome may occur in other neurodegenerative diseases where misfolded β-sheet-rich proteins accumulate.
  The EMBO Journal 01/2011; 30(15):3065-77. · 9.20 Impact Factor
• Source

  Available from: James Uphill

  Article: Genetic risk factors for variant Creutzfeldt-Jakob disease: a genome-wide association study.

  Simon Mead, Mark Poulter, James Uphill, John Beck, Jerome Whitfield, Thomas E F Webb, Tracy Campbell, Gary Adamson, Pelagia Deriziotis, Sarah J Tabrizi, Holger Hummerich, Claudio Verzilli, Michael P Alpers, John C Whittaker, John Collinge
  [show abstract] [hide abstract]
  ABSTRACT: Human and animal prion diseases are under genetic control, but apart from PRNP (the gene that encodes the prion protein), we understand little about human susceptibility to bovine spongiform encephalopathy (BSE) prions, the causal agent of variant Creutzfeldt-Jakob disease (vCJD). We did a genome-wide association study of the risk of vCJD and tested for replication of our findings in samples from many categories of human prion disease (929 samples) and control samples from the UK and Papua New Guinea (4254 samples), including controls in the UK who were genotyped by the Wellcome Trust Case Control Consortium. We also did follow-up analyses of the genetic control of the clinical phenotype of prion disease and analysed candidate gene expression in a mouse cellular model of prion infection. The PRNP locus was strongly associated with risk across several markers and all categories of prion disease (best single SNP [single nucleotide polymorphism] association in vCJD p=2.5 x 10(-17); best haplotypic association in vCJD p=1 x 10(-24)). Although the main contribution to disease risk was conferred by PRNP polymorphic codon 129, another nearby SNP conferred increased risk of vCJD. In addition to PRNP, one technically validated SNP association upstream of RARB (the gene that encodes retinoic acid receptor beta) had nominal genome-wide significance (p=1.9 x 10(-7)). A similar association was found in a small sample of patients with iatrogenic CJD (p=0.030) but not in patients with sporadic CJD (sCJD) or kuru. In cultured cells, retinoic acid regulates the expression of the prion protein. We found an association with acquired prion disease, including vCJD (p=5.6 x 10(-5)), kuru incubation time (p=0.017), and resistance to kuru (p=2.5 x 10(-4)), in a region upstream of STMN2 (the gene that encodes SCG10). The risk genotype was not associated with sCJD but conferred an earlier age of onset. Furthermore, expression of Stmn2 was reduced 30-fold post-infection in a mouse cellular model of prion disease. The polymorphic codon 129 of PRNP was the main genetic risk factor for vCJD; however, additional candidate loci have been identified, which justifies functional analyses of these biological pathways in prion disease.
  The Lancet Neurology 02/2009; 8(1):57-66. · 23.46 Impact Factor
• Source

  Available from: mpg.de

  Article: Prions and the proteasome.

  Pelagia Deriziotis, Sarah J Tabrizi
  [show abstract] [hide abstract]
  ABSTRACT: Prion diseases are fatal neurodegenerative disorders that include Creutzfeldt-Jakob disease in humans and bovine spongiform encephalopathy in animals. They are unique in terms of their biology because they are caused by the conformational re-arrangement of a normal host-encoded prion protein, PrPC, to an abnormal infectious isoform, PrPSc. Currently the precise mechanism behind prion-mediated neurodegeneration remains unclear. It is hypothesised than an unknown toxic gain of function of PrPSc, or an intermediate oligomeric form, underlies neuronal death. Increasing evidence suggests a role for the ubiquitin proteasome system (UPS) in prion disease. Both wild-type PrPC and disease-associated PrP isoforms accumulate in cells after proteasome inhibition leading to increased cell death, and abnormal beta-sheet-rich PrP isoforms have been shown to inhibit the catalytic activity of the proteasome. Here we review potential interactions between prions and the proteasome outlining how the UPS may be implicated in prion-mediated neurodegeneration.
  Biochimica et Biophysica Acta 12/2008; 1782(12):713-22. · 4.66 Impact Factor
• Source

  Available from: Heike Naumann

  Article: Disease-associated prion protein oligomers inhibit the 26S proteasome.

  Mark Kristiansen, Pelagia Deriziotis, Derek E Dimcheff, Graham S Jackson, Huib Ovaa, Heike Naumann, Anthony R Clarke, Fijs W B van Leeuwen, Victoria Menéndez-Benito, Nico P Dantuma, John L Portis, John Collinge, Sarah J Tabrizi
  [show abstract] [hide abstract]
  ABSTRACT: The mechanism of cell death in prion disease is unknown but is associated with the production of a misfolded conformer of the prion protein. We report that disease-associated prion protein specifically inhibits the proteolytic beta subunits of the 26S proteasome. Using reporter substrates, fluorogenic peptides, and an activity probe for the beta subunits, this inhibitory effect was demonstrated in pure 26S proteasome and three different cell lines. By challenge with recombinant prion and other amyloidogenic proteins, we demonstrate that only the prion protein in a nonnative beta sheet conformation inhibits the 26S proteasome at stoichiometric concentrations. Preincubation with an antibody specific for aggregation intermediates abrogates this inhibition, consistent with an oligomeric species mediating this effect. We also present evidence for a direct relationship between prion neuropathology and impairment of the ubiquitin-proteasome system (UPS) in prion-infected UPS-reporter mice. Together, these data suggest a mechanism for intracellular neurotoxicity mediated by oligomers of misfolded prion protein.
  Molecular Cell 05/2007; 26(2):175-88. · 14.18 Impact Factor