Mouse Models of ALS
Over the last 20 years, several transgenic mouse strains expressing human mutant SOD1 have been generated. These mice have been used to either examine disease mechanisms or trial potential therapeutic strategies for ALS, although the latter has led to questionable success (Perrin, 2014) (Tables 5, 6). The transgenic line harboring the Gly93 → Ala substitution (SOD1G93A) has been used most extensively (Gurney et al., 1994), followed by the SOD1G37R (Wong et al., 1995), SOD1G85R (Bruijn et al., 1997), SOD1G86R (Ripps et al., 1995) and SOD1D90A (Jonsson et al., 2006) models.
Table 5  SOD1, TDP-43 and FUS mouse models of ALS.
Mouse models  Promotor  CNS over-expression (fold)  Survival (months)  Inclusions  Motor Phenotype  MN loss  Denervation  References
SOD1  G93A  hSOD1  17  3.5–4.5  SOD1(+)  Yes  Yes  Yes  Gurney et al., 1994
s-G93A  hSOD1  8–10  8.3  hyaline  Yes  Yes  Yes  Gurney, 1997
G37R  hSOD1  4–12  5  SOD1(+)  Yes  Yes  Yes  Wong et al., 1995
G85R  hSOD1  0.2–1  8.5  SOD1(+) Ub(+)  Yes  Yes  Yes  Bruijn et al., 1997
TDP-43  A315T   PrP  3  5  TDP-43(–) Ub(+)  Yes  Yes  Yes  Wegorzewska et al., 2009
rNLS8   NEFH  –  2.6 off Dox  TDP-43(+)  Yes  Yes  Yes  Walker et al., 2015; Spiller et al., 2016a
M337VKNOCK-IN  –  No  24.5  No  No  No  Yes  Ebstein et al., 2019
G298SKNOCK-IN  –  No  24.5  No  No  Yes  Yes  Ebstein et al., 2019
TDP-43 KO  –  –  ns  No  Yes  Yes  Yes  Iguchi et al., 2013
FUS  hFUSWT   MAPT   2.6  No  No  No  Yes  Sharma et al., 2016
hFUSR521C   MAPT  4  12  No  No  Yes  Yes  Sharma et al., 2016
hFUSP525L   MAPT  4  12  No  Yes  Yes  Yes  Sharma et al., 2016
Table 6  Commonly used SOD1-transgenic mouse models of ALS and their phenotypes in relation to transgenic expression.
SOD1 mouse models  Transgene copies  SOD1 protein levels in the CNS (human/mouse)  Disease onset (days)  Survival (months)  References
B6SJL-TgN(SOD1-G93A)1Gur  34  17  90  3.5–4.5  Gurney et al., 1994; Alexander et al., 2004
SOD1-G93A Drop Copy#3  13  –  –  6  Alexander et al., 2004
SOD1-G93A Drop Copy#4  11  –  –  6.5  Alexander et al., 2004
B6SJL-TgN(SOD1-G93A)dl1Gur  10  8–10  168  8.3  Gurney, 1997
SOD1-G93A Drop Copy#1  4  –  –  21  Alexander et al., 2004
G37R  –  4–12  105  5  Wong et al., 1995; Haenggeli et al., 2007
G85R  –  0.2–1  240  8.5  Bruijn et al., 1997
G86R (M1 line)  –  –  90–120  4  Ripps et al., 1995
D90A  –  –  350  13.5  Jonsson et al., 2006
(–), unknown. 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).