期刊
NATURE COMMUNICATIONS
卷 7, 期 -, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/ncomms11253
关键词
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资金
- 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
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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