Neuronal expression of the ALS-linked P497H UBQLN2 variant was found to exacerbate TDP-43 pathology in a TDP-43 mutant mouse model [226], suggesting that additional hits might be needed to induce ALS/FTD and that both loss- and gain-of-function mechanisms are at play in UBQLN2-ALS/FTD [224]. This evidence concerns the gene TARDBP and frontotemporal dementia.