FUS and ALS. Shortly after the discovery of TDP-43 involvement in ALS, mutations in the fused in sarcoma (FUS) gene, encoding another RNA/DNA binding protein, were identified in ALS families (Xxxxxxxxxxx et al., 2009; Xxxxx et al., 2009). So far, 42 different FUS pathogenic mutations have been reported and these account for 4-6% of familial ALS cases (Xxxxxxxx and Xx-Xxxxxxx, 2011). The associated phenotype is consistent with a predominantly LMN involvement, early disease onset and rapid progression (Xxxxxxxxxx et al., 2010). FUS, also known as translocated in liposarcoma (TLS), is a ubiquitously expressed 526 amino acid protein originally described as a component of fusion oncogenes in human cancer (Rabbitts et al., 1993). It contains an N-terminal Gln-Gly-Ser-Tyr-rich domain, a Gly-rich domain, an RNA recognition motif, multiple Arg-Gly-Gly repeats and a C- terminal zinc finger motif (Lagier-Tourenne and Cleveland, 2009). Most pathogenic mutations are missense and cluster in the extreme C-terminus of the protein, a highly conserved region functioning as a nuclear localization signal (Mackenzie et al., 2010; Xxxxxxxx and Xxxxxxx, 2006). Although the protein resides mainly in the nucleus, analyses of brains and spinal cords from patients with FUS mutations reveals loss of nuclear FUS and ubiquitinated cytoplasmic inclusions positive for FUS, but negative for TDP-43 (Xxxxxxxx et al., 2010; Xxxxx et al., 2009). FUS is an RNA binding protein with structure and functions similar to TDP-43, raising the possibility that RNA misprocessing is a key feature in motor neuron degeneration. The protein shuttles between the nucleus and the cytoplasm (Xxxxxxxx et al., 1997) and is involved in cell proliferation, DNA repair, alternative splicing, transcription regulation, RNA and microRNA processing (Xxxxxxxxx, 2005; Xxxxxx-Xxxxxxxx et al., 2010; Xxx et al., 2006). The XXX xxxx knockout in inbred mice causes perinatal death accompanied by major B lymphocyte defects (Xxxxx et al., 2000), while only male sterility was reported in FUS deficient mice on an outbred background (Kuroda et al., 2000). Transgenic rats overexpressing ALS-associated mutant FUS develop progressive paralysis secondary to axonal degeneration and a significant loss of neurons in the frontal cortex and hippocampus recapitulating features of ALS and FTD (Xxxxx et al., 2011). Similar to TDP-43, expression of human wild-type FUS in rats is sufficient to induce cognitive deficits and mild neuronal loss at a more advanc...
