Journal
NATURE COMMUNICATIONS
Volume 7, Issue -, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/ncomms11253
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Funding
- Neurone Disease Research Institute of Australia
- National Health and Medical Research Council of Australia [1004670, 1107644, 1095215, 1092023, 1003032, 1034816, 1006141, 1030513, 630428]
- Snow Foundation
- European Community's Seventh Framework programme (FP7) [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, RC2-NS070-342]
- ALS Therapy Alliance
- ALS Association
- Milton Safenowitz Post-Doctoral Fellowship for ALS research from the ALS Association
- 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
- AriSLA (Healthcare research of the Ministry of Health)
- Medical Research Foundation [MRF-060-0003-RG-SMITH] Funding Source: researchfish
- National Health and Medical Research Council of Australia [1107644] Funding Source: NHMRC
- Australian Research Council [DE120102840] Funding Source: Australian Research Council
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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.
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