CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia

• 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
• Journal Title: Nature Communications
• Volume: Volume 7
• Publisher: Nature Publishing Group | 2016-04-01, Pages 11253-11253
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1038/ncomms11253
• Subjects: Biology, Genetics; Biology, Neuroscience; Health Sciences, General
• Keywords: Science & Technology; Multidisciplinary Sciences; UBIQUITIN-PROTEASOME SYSTEM; DNA-SEQUENCING DATA; LOBAR DEGENERATION; FAMILIAL ALS; PROTEIN; GENE; PATHOGENESIS; HOMEOSTASIS; PROTEOLYSIS

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.