PMC:6610326 / 34850-39576
Annnotations
{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/6610326","sourcedb":"PMC","sourceid":"6610326","source_url":"https://www.ncbi.nlm.nih.gov/pmc/6610326","text":"Mouse Models of ALS\nOver 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.\nTable 5 SOD1, TDP-43 and FUS mouse models of ALS.\nMouse models Promotor CNS over-expression (fold) Survival (months) Inclusions Motor Phenotype MN loss Denervation References\nSOD1 G93A hSOD1 17 3.5–4.5 SOD1(+) Yes Yes Yes Gurney et al., 1994\ns-G93A hSOD1 8–10 8.3 hyaline Yes Yes Yes Gurney, 1997\nG37R hSOD1 4–12 5 SOD1(+) Yes Yes Yes Wong et al., 1995\nG85R hSOD1 0.2–1 8.5 SOD1(+) Ub(+) Yes Yes Yes Bruijn et al., 1997\nTDP-43 A315T PrP 3 5 TDP-43(–) Ub(+) Yes Yes Yes Wegorzewska et al., 2009\nrNLS8 NEFH – 2.6 off Dox TDP-43(+) Yes Yes Yes Walker et al., 2015; Spiller et al., 2016a\nM337VKNOCK-IN – No 24.5 No No No Yes Ebstein et al., 2019\nG298SKNOCK-IN – No 24.5 No No Yes Yes Ebstein et al., 2019\nTDP-43 KO – – ns No Yes Yes Yes Iguchi et al., 2013\nFUS hFUSWT MAPT 2.6 No No No Yes Sharma et al., 2016\nhFUSR521C MAPT 4 12 No No Yes Yes Sharma et al., 2016\nhFUSP525L MAPT 4 12 No Yes Yes Yes Sharma et al., 2016\nTable 6 Commonly used SOD1-transgenic mouse models of ALS and their phenotypes in relation to transgenic expression.\nSOD1 mouse models Transgene copies SOD1 protein levels in the CNS (human/mouse) Disease onset (days) Survival (months) References\nB6SJL-TgN(SOD1-G93A)1Gur 34 17 90 3.5–4.5 Gurney et al., 1994; Alexander et al., 2004\nSOD1-G93A Drop Copy#3 13 – – 6 Alexander et al., 2004\nSOD1-G93A Drop Copy#4 11 – – 6.5 Alexander et al., 2004\nB6SJL-TgN(SOD1-G93A)dl1Gur 10 8–10 168 8.3 Gurney, 1997\nSOD1-G93A Drop Copy#1 4 – – 21 Alexander et al., 2004\nG37R – 4–12 105 5 Wong et al., 1995; Haenggeli et al., 2007\nG85R – 0.2–1 240 8.5 Bruijn et al., 1997\nG86R (M1 line) – – 90–120 4 Ripps et al., 1995\nD90A – – 350 13.5 Jonsson et al., 2006\n(–), 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, 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