Williams, Kelly L.Kost, JasonBrown, Robert H. Jr.Landers, John EBlair, Ian P.2022-08-232022-08-232016-04-152016-10-05Nat Commun. 2016 Apr 15;7:11253. doi: 10.1038/ncomms11253. <a href="http://dx.doi.org/10.1038/ncomms11253">Link to article on publisher's site</a>2041-1723 (Linking)10.1038/ncomms1125327080313https://hdl.handle.net/20.500.14038/40057<p>Full author list omitted for brevity. For full list of authors see article.</p>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.en-UShttp://creativecommons.org/licenses/by/4.0/Computational BiologyGenomicsMolecular and Cellular NeuroscienceNervous System DiseasesNeurologyJournal Articlehttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=3866&amp;context=oapubs&amp;unstamped=1https://escholarship.umassmed.edu/oapubs/28619233080oapubs/2861