Fig. 1.

Overexpression of mutant human TDP-43 leads to a dose-dependent motor phenotype. a Modified Thy-1.2 expression vector used to generate mutant (p.M337V) human TDP-43 (hTDP-43) transgenic mice. b TARDBP mRNA expression levels measured in brain by qRT-PCR for the different mutant TDP-43 (Mt-TAR) mouse lines. Mt-TAR6/6 expression levels were comparable to those measured in wild-type TDP-43 mice (Wt-TAR4/4 and Wt-TAR4) as described earlier. c Overexpression of mutant TDP-43 induced an abnormal hindlimb reflex (arrows) at variable ages dependent on the TDP-43 dose that was absent in non-transgenic (Ntg) mice and Mt-TAR5/5 mice expressing a low TDP-43 dose. d TDP-43 dose for both mutant (Mt-TAR6/6, n = 8; Mt-TAR5/6, n = 7; Mt-TAR6, n = 12) and wild-type (Wt-TAR4/4, n = 6; Wt-TAR4, n = 8; Wt-TAR6/6, n = 4) TDP-43 mice showed a log–log correlation with the age of onset or the age where the abnormal hindlimb reflex was first noticed (R ² = 0.97). e Typical example of an end-stage paralysis in Mt-TAR6/6 mice (Movie S1). f About 5 % of end-stage hemizygous Mt-TAR6 mice developed severe paralysis of the hindlimbs and acquired a swimming gait. g Kaplan–Meier analysis for different mutant and wild-type TDP-43 mice revealing a reduced lifespan for transgenic mice compared to Ntg littermates. Homozygous mutant TDP-43 mice show higher mortality compared to wild-type TDP-43 mice, which is reflected by an average survival of 17 days for Mt-TAR6/6 compared to 24 days for Wt-TAR4/4 mice (Mt-TAR6/6, n = 29; Wt-TAR4/4, n = 49). Double hemizygous Mt-TAR5/6 mice have an average survival of 9.3 months compared to 16.4 and 16.6 months for Mt-TAR6 and Wt-TAR4 mice, respectively (Ntg, n = 69; Mt-TAR6, n = 72; Wt-TAR4, n = 46; Mt-TAR5/6, n = 31). [24]