CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia

Topic: Disease mechanisms in lab and animal studies

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.

Key findings

• 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.

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Study details

• Evidence strengthModerate

Read the original

• DOI: 10.1038/ncomms11253
• PubMed: 27080313
• Original source →

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@article{williams2016-27080313,
  author  = {Williams, K. L. and Topp, S. and Yang, S. and Smith, B. and Fifita, J. A. and Warraich, S. T. and Zhang, K. Y. and Farrawell, N. and others},
  title   = {{CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia}},
  journal = {Nature communications},
  year    = {2016},
  doi     = {10.1038/ncomms11253},
  pmid    = {27080313},
  url     = {https://doi.org/10.1038/ncomms11253}
}

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