The B6SJL-TgN(SOD1-G93A)1Gur mouse (Gurney et al., 1994) carries 25 ± 1.5 copies of the transgene within chromosome 12 and as a result, it expresses very high levels of human mutant SOD1G93A (Alexander et al., 2004). Whilst these significant levels of overexpression are criticized as a major limitation (Alexander et al., 2004), these animals remain the most widely used mouse model for therapeutic studies in ALS (Gurney et al., 1994). These SOD1G93A mice become paralyzed in the hindlimbs as a result of MN loss from the spinal cord, resulting in death by 5 months of age. Another variant of this model, B6SJL-TgN(SOD1-G93A)dl1Gur, possesses fewer copies of the transgene; 8 ± 1.5 (Gurney, 1997; Alexander et al., 2004)2. This “low-copy” mouse, hereafter referred to as “G93A-slow” (s-SOD1G93A), develops a slower disease course in comparison, where paralysis begins at 6–8.5 months of age (Alexander et al., 2004; Muller et al., 2008; Acevedo-Arozena et al., 2011). In addition, several other “low-copy” mouse lines have subsequently been generated, with even fewer copies of the human SOD1G93A transgene. These models also exhibit greater life spans compared to the higher copy lines (Alexander et al., 2004) (Table 6). Similarly, four lines of mice expressing another SOD1 mutant, SOD1G37R, at different levels (5–14 times) have been produced, with variable phenotypes (Wong et al., 1995). Multiple mouse models based on transgenic expression of wild type or mutant TDP-43 have also been generated (Philips and Rothstein, 2015) (Table 5). Overexpressing human TDP-43 with a defective nuclear localization signal (NLS) in mice – in the absence of an ALS mutation – results in cytoplasmic expression of hTDP-43 and nuclear TDP-43 clearance. This results in a severe motor phenotype and reduced survival in the resulting ‘rNLS8’ mice compared to littermate controls (Walker et al., 2015). Several mouse models also exist based on transgenic expression of mutant FUS (Table 5). These mice display progressive, age- and mutation-dependent degeneration that also model aspects of ALS (Sharma et al., 2016). Furthermore, several newer models based on the C9orf72 repeat expansion have also been produced, although the phenotypes are more reminiscent of FTD rather than ALS (Batra and Lee, 2017).