USP14 might also exert alternative functions that are dependent on substrate or cellular context: In a cellular model of prion disease, overexpression of catalytically inactive USP14 reduced accumulation of prion protein (Hommaet al., 2015), whereas in a cellular Huntington’s disease model overexpression of catalytically inactive USP14 had no effect on huntingtin protein aggregates (Hyrskyluotoet al., 2014). The gene discussed is HTT; the disease is prion disease.