Williams KL, Topp S, Yang S, Smith B, Fifita JA, Warraich ST, Zhang KY, Farrawell N, Vance C, Hu X, Chesi A, Leblond CS, Lee A, Rayner SL, Sundaramoorthy V, Dobson-Stone C, Molloy MP, van Blitterswijk M, Dickson DW, Petersen RC, Graff-Radford NR, Boeve BF, Murray ME, Pottier C, Don E, Winnick C, McCann EP, Hogan A, Daoud H, Levert A, Dion PA, Mitsui J, Ishiura H, Takahashi Y, Goto J, Kost J, Gellera C, Gkazi AS, Miller J, Stockton J, Brooks WS, Boundy K, Polak M, Muñoz-Blanco JL, Esteban-Pérez J, Rábano A, Hardiman O, Morrison KE, Ticozzi N, Silani V, de Belleroche J, Glass JD, Kwok JB, Guillemin GJ, Chung RS, Tsuji S, Brown RH Jr, García-Redondo A, Rademakers R, Landers JE, Gitler AD, Rouleau GA, Cole NJ, Yerbury JJ, Atkin JD, Shaw CE, Nicholson GA, Blair IP. 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.

    References:

    Araki W, Minegishi S, Motoki K, Kume H, Hohjoh H, Araki YM, Tamaoka A. Disease-Associated Mutations of TDP-43 Promote Turnover of the Protein Through the Proteasomal Pathway. Mol Neurobiol. 2014 Jan 30; PubMed.

    Scotter EL, Vance C, Nishimura AL, Lee YB, Chen HJ, Urwin H, Sardone V, Mitchell JC, Rogelj B, Rubinsztein DC, Shaw CE. 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