La Trobe
46438_Williams,K_2016.pdf (709.26 kB)

CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia

Download (709.26 kB)
journal contribution
posted on 2023-02-15, 22:44 authored by KL Williams, S Topp, S Yang, B Smith, JA Fifita, ST Warraich, KY Zhang, N Farrawell, C Vance, X Hu, A Chesi, CS Leblond, A Lee, SL Rayner, V Sundaramoorthy, C Dobson-Stone, MP Molloy, M van Blitterswijk, DW Dickson, RC Petersen, NR Graff-Radford, BF Boeve, ME Murray, C Pottier, E Don, C Winnick, EP McCann, A Hogan, H Daoud, A Levert, PA Dion, J Mitsui, H Ishiura, Y Takahashi, J Goto, J Kost, C Gellera, AS Gkazi, J Miller, J Stockton, WS Brooks, K Boundy, M Polak, JL Munoz-Blanco, J Esteban-Perez, A Rabano, O Hardiman, KE Morrison, N Ticozzi, V Silani, J de Belleroche, JD Glass, JBJ Kwok, GJ Guillemin, RS Chung, S Tsuji, RH Brown, A Garcia-Redondo, R Rademakers, JE Landers, AD Gitler, GA Rouleau, NJ Cole, JJ Yerbury, Julie AtkinJulie Atkin, CE Shaw, GA Nicholson, IP Blair
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.


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.vB.), 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 Investigacion 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 x 1,000'-Healthcare research of the Ministry of Health, grants EXOMEFALS 2009, NOVALS 2012).


Publication Date



Nature Communications





Article Number



8p. (p. 1-8)


Springer Nature



Rights Statement

This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit

Usage metrics

    Journal Articles


    No categories selected



    Ref. manager