. CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia. Nat Commun. 2016 Apr 15;7:11253. PubMed.


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  1. Williams et al. revealed the novel ALS/FTD-associated gene CCNF, which encodes cyclin F protein, a component of the SCF E3 ubiquitin-ligase complex. I find this paper particularly intriguing for two reasons. First, the paper clearly indicates that the ubiquitin-proteasome system is intimately involved in the pathological mechanism of ALS/FTD. Second, the frequencies of CCNF mutations are relatively high and comparable to those of TARDBP.

    The study provided evidence that various mutations of CCNF impair ubiquitin-mediated proteasomal degradation, which is suggested to be due to abnormal ubiquitination or transport to the proteasome. Previous studies, including ours, have shown that full-length TDP-43 is primarily degraded via the proteasomal pathway (Araki et al., 2014; Scotter et al., 2014). It remains to be elucidated whether cyclin F-SCF complex is mechanistically involved in the pathological accumulation of TDP-43, and what pathological features are observed in the patients with CCNF mutations.


    . Disease-Associated Mutations of TDP-43 Promote Turnover of the Protein Through the Proteasomal Pathway. Mol Neurobiol. 2014 Jan 30; PubMed.

    . Differential roles of the ubiquitin proteasome system and autophagy in the clearance of soluble and aggregated TDP-43 species. J Cell Sci. 2014 Mar 15;127(Pt 6):1263-78. Epub 2014 Jan 14 PubMed.

    View all comments by Wataru Araki

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  1. New Gene Strengthens Link Between ALS and FTD