CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia
UMass Chan AffiliationsDepartment of Neurology
Document TypeJournal Article
Molecular and Cellular Neuroscience
Nervous System Diseases
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AbstractAmyotrophic 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.
SourceNat Commun. 2016 Apr 15;7:11253. doi: 10.1038/ncomms11253. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/40057
Full author list omitted for brevity. For full list of authors see article.
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Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by/4.0/