These mice are useful in studying amyotrophic lateral sclerosis (ALS) / frontotemporal lobar degeneration (FTLD). The phenotype of these mice is expected to be as described in Walker et al. 2015 Acta Neuropathol 130:643; details below.

Stock No. 028413 is the regulatable control double transgenic line for the rNLS8 model (Stock No. 028412; described below). Stock No. 028413 is created by breeding NEFH-tTA line 8 (Stock No. 025397) with TRE-promoter-driven human TDP-43 wildtype transgenic mice (tetO-hTDP-43-WT line 12 ; Stock No. 016841). On a mixed C57BL/6J x C3HeJ F1 genetic background, mice hemizygous for NEFH-tTA and hemizygous for tetO-hTDP-43-WT exhibit broad nuclear hTDP-43-WT expression in the brain and spinal cord, without the formation of cytoplasmic TDP-43 pathology.

Stock No. 028412 is the regulatable NLS (rNLS8) double transgenic line created by breeding NEFH-tTA line 8 (Stock No. 025397) with TRE-promoter-driven cytoplasmic-insoluble human TDP-43ΔNLS transgenic mice (tetO-hTDP-43-ΔNLS line 4 ; Stock No. 014650). On a mixed C57BL/6J x C3HeJ F1 genetic background, mice hemizygous for NEFH-tTA and hemizygous for tetO-hTDP-43-ΔNLS exhibit lethal characteristics of amyotrophic lateral sclerosis (ALS) / frontotemporal lobar degeneration (FTLD) when maintained in the absence of the tetracycline analog, doxycycline (dox). Specifically, they exhibit widespread, high levels of hTDP-43ΔNLS expression in neurons of both the brain and spinal cord (SC) as early as 1 week off-dox. The brain/SC combination of hTDP-43-ΔNLS expression accounts for the spinal motor neuron loss and muscle denervation; resulting in a rapid, robust and progressive neurodegenerative ALS-like phenotype (including motor deficits, denervation of neuromuscular junctions, motor neuron loss and premature death at ~8-20 weeks). Upon administration of dox, the observed TDP-43 pathology and functional deficits were found to be largely reversible, even after neurodegeneration was underway (~8 weeks of hTDP-43-ΔNLS expression).

Importantly, the donating investigator reports that the human NEFH promoter in NEFH-tTA line 8 drives slightly higher levels of tTA expression in the cortex compared to their experiences with the mouse Camk2a promoter used in Camk2a-tTA mice (greater than ~10-fold higher than endogenous NEFH versus ~8-fold higher than endogenous CAMK2A). In addition, the human NEFH promoter directs tTA expression in spinal cord (whereas the mouse Camk2a promoter did not).