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  • 1
    Publication Date: 2013-08-02
    Description: Prion infections cause lethal neurodegeneration. This process requires the cellular prion protein (PrP(C); ref. 1), which contains a globular domain hinged to a long amino-proximal flexible tail. Here we describe rapid neurotoxicity in mice and cerebellar organotypic cultured slices exposed to ligands targeting the alpha1 and alpha3 helices of the PrP(C) globular domain. Ligands included seven distinct monoclonal antibodies, monovalent Fab1 fragments and recombinant single-chain variable fragment miniantibodies. Similar to prion infections, the toxicity of globular domain ligands required neuronal PrP(C), was exacerbated by PrP(C) overexpression, was associated with calpain activation and was antagonized by calpain inhibitors. Neurodegeneration was accompanied by a burst of reactive oxygen species, and was suppressed by antioxidants. Furthermore, genetic ablation of the superoxide-producing enzyme NOX2 (also known as CYBB) protected mice from globular domain ligand toxicity. We also found that neurotoxicity was prevented by deletions of the octapeptide repeats within the flexible tail. These deletions did not appreciably compromise globular domain antibody binding, suggesting that the flexible tail is required to transmit toxic signals that originate from the globular domain and trigger oxidative stress and calpain activation. Supporting this view, various octapeptide ligands were not only innocuous to both cerebellar organotypic cultured slices and mice, but also prevented the toxicity of globular domain ligands while not interfering with their binding. We conclude that PrP(C) consists of two functionally distinct modules, with the globular domain and the flexible tail exerting regulatory and executive functions, respectively. Octapeptide ligands also prolonged the life of mice expressing the toxic PrP(C) mutant, PrP(Delta94-134), indicating that the flexible tail mediates toxicity in two distinct PrP(C)-related conditions. Flexible tail-mediated toxicity may conceivably play a role in further prion pathologies, such as familial Creutzfeldt-Jakob disease in humans bearing supernumerary octapeptides.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sonati, Tiziana -- Reimann, Regina R -- Falsig, Jeppe -- Baral, Pravas Kumar -- O'Connor, Tracy -- Hornemann, Simone -- Yaganoglu, Sine -- Li, Bei -- Herrmann, Uli S -- Wieland, Barbara -- Swayampakula, Mridula -- Rahman, Muhammad Hafizur -- Das, Dipankar -- Kav, Nat -- Riek, Roland -- Liberski, Pawel P -- James, Michael N G -- Aguzzi, Adriano -- England -- Nature. 2013 Sep 5;501(7465):102-6. doi: 10.1038/nature12402. Epub 2013 Jul 31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Neuropathology, University Hospital Zurich, Schmelzbergstrasse 12, CH-8091 Zurich, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23903654" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Antibodies/*immunology/*toxicity ; Antibodies, Monoclonal/immunology/toxicity ; Binding Sites, Antibody ; Calpain/metabolism ; Cerebellum ; Creutzfeldt-Jakob Syndrome/metabolism ; Cross-Linking Reagents ; Epitope Mapping ; Female ; Immunoglobulin Fab Fragments/immunology/toxicity ; In Vitro Techniques ; Ligands ; Male ; Membrane Glycoproteins/metabolism ; Mice ; Molecular Sequence Data ; NADPH Oxidase/metabolism ; Neurodegenerative Diseases/metabolism ; Oxidative Stress ; *Pliability ; PrPC Proteins/chemistry/genetics/immunology ; Prions/*chemistry/genetics/*immunology ; Reactive Oxygen Species/metabolism ; Sequence Deletion/genetics ; Single-Chain Antibodies/immunology/toxicity
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2012-01-31
    Description: Glioblastoma multiforme (GBM) is a lethal brain tumour in adults and children. However, DNA copy number and gene expression signatures indicate differences between adult and paediatric cases. To explore the genetic events underlying this distinction, we sequenced the exomes of 48 paediatric GBM samples. Somatic mutations in the H3.3-ATRX-DAXX chromatin remodelling pathway were identified in 44% of tumours (21/48). Recurrent mutations in H3F3A, which encodes the replication-independent histone 3 variant H3.3, were observed in 31% of tumours, and led to amino acid substitutions at two critical positions within the histone tail (K27M, G34R/G34V) involved in key regulatory post-translational modifications. Mutations in ATRX (alpha-thalassaemia/mental retardation syndrome X-linked) and DAXX (death-domain associated protein), encoding two subunits of a chromatin remodelling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres, were identified in 31% of samples overall, and in 100% of tumours harbouring a G34R or G34V H3.3 mutation. Somatic TP53 mutations were identified in 54% of all cases, and in 86% of samples with H3F3A and/or ATRX mutations. Screening of a large cohort of gliomas of various grades and histologies (n = 784) showed H3F3A mutations to be specific to GBM and highly prevalent in children and young adults. Furthermore, the presence of H3F3A/ATRX-DAXX/TP53 mutations was strongly associated with alternative lengthening of telomeres and specific gene expression profiles. This is, to our knowledge, the first report to highlight recurrent mutations in a regulatory histone in humans, and our data suggest that defects of the chromatin architecture underlie paediatric and young adult GBM pathogenesis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schwartzentruber, Jeremy -- Korshunov, Andrey -- Liu, Xiao-Yang -- Jones, David T W -- Pfaff, Elke -- Jacob, Karine -- Sturm, Dominik -- Fontebasso, Adam M -- Quang, Dong-Anh Khuong -- Tonjes, Martje -- Hovestadt, Volker -- Albrecht, Steffen -- Kool, Marcel -- Nantel, Andre -- Konermann, Carolin -- Lindroth, Anders -- Jager, Natalie -- Rausch, Tobias -- Ryzhova, Marina -- Korbel, Jan O -- Hielscher, Thomas -- Hauser, Peter -- Garami, Miklos -- Klekner, Almos -- Bognar, Laszlo -- Ebinger, Martin -- Schuhmann, Martin U -- Scheurlen, Wolfram -- Pekrun, Arnulf -- Fruhwald, Michael C -- Roggendorf, Wolfgang -- Kramm, Christoph -- Durken, Matthias -- Atkinson, Jeffrey -- Lepage, Pierre -- Montpetit, Alexandre -- Zakrzewska, Magdalena -- Zakrzewski, Krzystof -- Liberski, Pawel P -- Dong, Zhifeng -- Siegel, Peter -- Kulozik, Andreas E -- Zapatka, Marc -- Guha, Abhijit -- Malkin, David -- Felsberg, Jorg -- Reifenberger, Guido -- von Deimling, Andreas -- Ichimura, Koichi -- Collins, V Peter -- Witt, Hendrik -- Milde, Till -- Witt, Olaf -- Zhang, Cindy -- Castelo-Branco, Pedro -- Lichter, Peter -- Faury, Damien -- Tabori, Uri -- Plass, Christoph -- Majewski, Jacek -- Pfister, Stefan M -- Jabado, Nada -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2012 Jan 29;482(7384):226-31. doi: 10.1038/nature10833.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉McGill University and Genome Quebec Innovation Centre, Montreal, Quebec H3A 1A4, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22286061" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/genetics ; Base Sequence ; Child ; Chromatin/*genetics/metabolism ; Chromatin Assembly and Disassembly/*genetics ; DNA Helicases/genetics ; DNA Mutational Analysis ; Exome/genetics ; Gene Expression Profiling ; Glioblastoma/*genetics ; Histones/*genetics/metabolism ; Humans ; Molecular Sequence Data ; Mutation/*genetics ; Nuclear Proteins/genetics ; Telomere/genetics ; Tumor Suppressor Protein p53/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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