CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia

• Type of Material: Article
• Authors: Kelly L. Williams, Macquarie University; Simon Topp, Kings College London; Shu Yang, Macquarie University; Bradley Smith, Kings College London; Jennifer A. Fifita, Macquarie University; Sadaf T. Warraich, Macquarie University; Katharine Y. Zhang, Macquarie University; Natalie Farrawell, University of Wollongong; Caroline Vance, Kings College London; Xun Hu, Kings College London; Alessandra Chesi, Stanford University; Claire S. Leblond, McGill University; Albert Lee, Macquarie University; Stephanie L. Rayner, Macquarie University; Vinod Sundaramoorthy, Macquarie University; Carol Dobson-Stone, Neuroscience Research Australia; Mark P. Molloy, Macquarie University; Marka van Blitterswijk, Mayo Clinic Florida; Dennis W. Dickson, Mayo Clinic Florida; Ronald C. Petersen, Mayo Clinic Rochester; Neill R. Graff-Radford, Mayo Clinic Florida; Bradley F. Boeve, Mayo Clinic Rochester; Melissa E. Murray, Mayo Clinic Florida; Cyril Pottier, Mayo Clinic Florida; Emily Don, Macquarie University; Claire Winnick, Macquarie University; Emily P. McCann, Macquarie University; Alison Hogan, Macquarie University; Hussein Daoud, McGill University; Annie Levert, McGill University; Patrick A. Dion, McGill University; Jun Mitsui, University of Tokyo; Hiroyuki Ishiura, University of Tokyo; Yuji Takahashi, University of Tokyo; Jun Goto, University of Tokyo; Jason Kost, Worcester Polytechnic Institute; Cinzia Gellera, Fondazione IRCCS Istituto Neurologico 'Carlo Besta'; Athina Soragia Gkazi, Kings College London; Jack Miller, Kings College London; Joanne Stockton, University of Birmingham; William S. Brooks, Neuroscience Research Australia; Karyn Boundy, Queen Elizabeth Hospital; Meraida Polak, Emory University; José Luis Muñoz-Blanco, Instituto de Investigación Hospital Gregorio Marañón de Madrid; Jesús Esteban-Pérez, Instituto de Investigación Hospital 12 de Octubre de Madrid; Alberto Rábano, Fundación CIEN; Orla Hardiman, Trinity College Dublin; Karen E. Morrison, University of Birmingham; Nicola Ticozzi, IRCCS Istituto Auxologico Italiano; Vincenzo Silani, IRCCS Istituto Auxologico Italiano; Jacqueline de Belleroche, Univ London Imperial Coll Sci Technol & Med; Jonathan Glass, Emory University; John B.J. Kwok, Neuroscience Research Australia; Gilles J. Guillemin, Macquarie University; Roger S. Chung, Macquarie University; Shoji Tsuji, University of Tokyo; Robert H. Brown, University of Massachusetts; Alberto García-Redondo, Instituto de Investigación Hospital 12 de Octubre de Madrid; Rosa Rademakers, Mayo Clinic Florida; John E. Landers, University of Massachusetts; Aaron D. Gitler, Stanford University; Guy A. Rouleau, McGill University; Nicholas J. Cole, Macquarie University; Justin J. Yerbury, University of Wollongong; Julie D. Atkin, Macquarie University; Christopher E. Shaw, Kings College London; Garth A. Nicholson, Macquarie University; Ian P. Blair, Macquarie University
• Language: English
• Date: 2016-04-01
• Publisher: Nature Publishing Group
• Publication Version: Final Published Version
• Copyright Statement: © 2016, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/ncomms11253
• Title of Journal or Parent Work: Nature Communications
• ISSN: 2041-1723
• Volume: 7
• Start Page: 11253
• End Page: 11253
• Grant/Funding Information: This work was funded by the Motor Neurone Disease Research Institute of Australia (grants to I.P.B. and J.D.A. and a Bill Gole fellowship to K.L.W.), National Health and Medical Research Council of Australia (1004670, 1107644, 1095215, 1092023, 1003032, 1034816, 1006141, 1030513 and 630428), The Snow Foundation, European Community’s Seventh Framework programme (FP7/2007–2013) under the grant agreement number 259867, Medical Research Council, Motor Neuron Disease Association (UK), Heaton-Ellis Trust, NIH/NINDS (1DP2OD0044171, R01 NS065317, P50 AG016574, R01 NS076471, R01 AG026251, P50 NS72187, P01 AG03949, R01NS073873, 1R01NS050557 and RC2-NS070-342), ALS Therapy Alliance, ALS Association, the Milton Safenowitz Post-Doctoral Fellowship for ALS research from the ALS Association (to M.v B.), the Mangurian Foundation, CurePSP, Project ALS, P2ALS, Angel Fund, Pierre L. de Bourgknecht ALS Research Foundation, Al-Athel ALS Research Foundation, CIHR (208973), MDA (153959), ARC Discovery Early Career Award (DE120102840), Fondo de Investigación Sanitaria of Spain (EC08/00049; PI10/00092), FUNDELA (Spanish foundation for the development of ALS research), Mireia Barneda project ‘No llores, no te rindas’, Midlands Neuroscience Teaching and Research Fund, and AriSLA (co-financed with support of ‘5 × 1,000’—Healthcare research of the Ministry of Health, grants EXOMEFALS 2009, NOVALS 2012).
• Keywords: Science & Technology; PATHOGENESIS; UBIQUITIN-PROTEASOME SYSTEM; Multidisciplinary Sciences; FAMILIAL ALS; PROTEOLYSIS; HOMEOSTASIS; LOBAR DEGENERATION; PROTEIN; GENE; DNA-SEQUENCING DATA
• Research Categories: Biology, Genetics; Biology, Neuroscience; Health Sciences, General

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping, fatal neurodegenerative disorders in which the molecular and pathogenic basis remains poorly understood. Ubiquitinated protein aggregates, of which TDP-43 is a major component, are a characteristic pathological feature of most ALS and FTD patients. Here we use genome-wide linkage analysis in a large ALS/FTD kindred to identify a novel disease locus on chromosome 16p13.3. Whole-exome sequencing identified a CCNF missense mutation at this locus. Interrogation of international cohorts identified additional novel CCNF variants in familial and sporadic ALS and FTD. Enrichment of rare protein-altering CCNF variants was evident in a large sporadic ALS replication cohort. CCNF encodes cyclin F, a component of an E3 ubiquitin-protein ligase complex (SCFCyclin F). Expression of mutant CCNF in neuronal cells caused abnormal ubiquitination and accumulation of ubiquitinated proteins, including TDP-43 and a SCFCyclin F substrate. This implicates common mechanisms, linked to protein homeostasis, underlying neuronal degeneration.