Department of Neurology
Computational Biology | Genomics | Molecular and Cellular Neuroscience | Nervous System Diseases | Neurology
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.
DOI of Published Version
Nat Commun. 2016 Apr 15;7:11253. doi: 10.1038/ncomms11253. Link to article on publisher's site
Williams KL, Kost J, Brown RH, Landers JE, Blair IP. (2016). CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia. Open Access Publications by UMMS Authors. https://doi.org/10.1038/ncomms11253. Retrieved from https://escholarship.umassmed.edu/oapubs/2861
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