The E3 Ubiquitin Ligase SCF Cyclin F Promotes Sequestosome-1/p62 Insolubility and Foci Formation and is Dysregulated in ALS and FTD Pathogenesis.

Amyotrophic lateral sclerosis (ALS)- and frontotemporal dementia (FTD)-linked mutations in CCNF have been shown to cause dysregulation to protein homeostasis. CCNF encodes for cyclin F, which is part of the cyclin F-E3 ligase complex SCFcyclinF known to ubiquitylate substrates for proteasomal degradation. In this study, we identified a function of cyclin F to regulate substrate solubility and show how cyclin F mechanistically underlies ALS and FTD disease pathogenesis. We demonstrated that ALS and FTD-associated protein sequestosome-1/p62 (p62) was a canonical substrate of cyclin F which was ubiquitylated by the SCFcyclinF complex. We found that SCFcyclin F ubiquitylated p62 at lysine(K)281, and that K281 regulated the propensity of p62 to aggregate. Further, cyclin F expression promoted the aggregation of p62 into the insoluble fraction, which corresponded to an increased number of p62 foci. Notably, ALS and FTD-linked mutant cyclin F p.S621G aberrantly ubiquitylated p62, dysregulated p62 solubility in neuronal-like cells, patient-derived fibroblasts and induced pluripotent stem cells and dysregulated p62 foci formation. Consistently, motor neurons from patient spinal cord tissue exhibited increased p62 ubiquitylation. We suggest that the p.S621G mutation impairs the functions of cyclin F to promote p62 foci formation and shift p62 into the insoluble fraction, which may be associated to aberrant mutant cyclin F-mediated ubiquitylation of p62. Given that p62 dysregulation is common across the ALS and FTD spectrum, our study provides insights into p62 regulation and demonstrates that ALS and FTD-linked cyclin F mutant p.S621G can drive p62 pathogenesis associated with ALS and FTD.

A multicenter study of preventable contact burns from glass fronted gas fireplaces.

Glass fronted gas fireplaces (GFGFs) have exterior surfaces that can reach extremely high temperatures. Burn injuries from contact with the glass front can be severe with long-term sequelae. The Consumer Product Safety Commission reported that these injuries are uncommon, whereas single-center studies indicate a much higher frequency. The purpose of this multi-institutional study was to determine the magnitude and severity of GFGF injuries in North America. Seventeen burn centers elected to participate in this retrospective chart review. Chart review identified 402 children ≤10 years of age who sustained contact burns from contact with GFGF, who were seen or admitted to the study hospitals from January 2006 to December 2010. Demographic, burn, treatment, and financial data were collected. The mean age of the study group was 16.8 ± 13.3 months. The majority suffered burns to their hands (396, 98.5%), with burns to the face being the second, much less common site (14, 3.5%). Two hundred and sixty-nine required rehabilitation therapy (66.9%). The number of GFGF injuries reported was 20 times greater than the approximately 30 injuries estimated by the Consumer Product Safety Commission's 10-year review. For the affected children, these injuries are painful, often costly and occasionally can lead to long-term sequelae. Given that less than a quarter of burn centers contributed data, the injury numbers reported herein support a need for broader safety guidelines for gas fireplaces in order to have a significant impact on future injuries.