CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia Academic Article uri icon

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 (SCF(Cyclin F)). Expression of mutant CCNF in neuronal cells caused abnormal ubiquitination and accumulation of ubiquitinated proteins, including TDP-43 and a SCF(Cyclin F) substrate. This implicates common mechanisms, linked to protein homeostasis, underlying neuronal degeneration.

authors

  • Williams, KL
  • Topp, S
  • Yang, S
  • Smith, B
  • Fifita, JA
  • Warraich, ST
  • Zhang, KY
  • Farrawell, N
  • Vance, C
  • Hu, X
  • Chesi, A
  • Leblond, CS
  • Lee, A
  • Rayner, SL
  • Sundaramoorthy, V
  • Dobson-Stone, C
  • Molloy, MP
  • van Blitterswijk, M
  • Dickson, DW
  • Petersen, RC
  • Graff-Radford, NR
  • Boeve, BF
  • Murray, ME
  • Pottier, C
  • Don, E
  • Winnick, C
  • McCann, EP
  • Hogan, A
  • Daoud, H
  • Levert, A
  • Dion, PA
  • Mitsui, J
  • Ishiura, H
  • Takahashi, Y
  • Goto, J
  • Kost, J
  • Gellera, C
  • Gkazi, AS
  • Miller, J
  • Stockton, J
  • Brooks, WS
  • Boundy, K
  • Polak, M
  • Munoz-Blanco, JL
  • Esteban-Perez, J
  • Rabano, A
  • Hardiman, O
  • Morrison, KE
  • Ticozzi, N
  • Silani, V
  • de Belleroche, J
  • Glass, JD
  • Kwok, JBJ
  • Guillemin, GJ
  • Chung, RS
  • Tsuji, S
  • Brown, RH
  • Garcia-Redondo, A
  • Rademakers, R
  • Landers, JE
  • Gitler, AD
  • Rouleau, GA
  • Cole, NJ
  • Yerbury, JJ
  • Atkin, JD
  • Shaw, CE
  • Nicholson, GA
  • Blair, IP

publication date

  • 2016

has subject area