Fig. 4

Suppressing the hTDP-43ΔNLS transgene restores endogenous mTDP-43 and halts MN loss in both young and aged rNLS8 mice. a Representative pictures of lumbar SC of young (left) and aged (right) rNLS8 mice at 6 wks off Dox show high, cytoplasmic expression of hTDP-43 (green). b After 12 wks back on Dox, both young and aged rNLS8 mice show a clearance of this cytoplasmic hTDP-43. c When the same cryosections were stained with a TDP-43 antibody that labels both mouse and human TDP-43 or total (ttl) TDP-43 (red), nuclear clearance of TDP-43 is obvious in both young and aged rNLS8 mice at 6 wks off Dox. d After 12 wks of transgene suppression, there is a return of endogenous mTDP-43 to the nucleus in young and aged mice. Scale bars = 100 μm. e Representative immunoblots showing RIPA-soluble hTDP-43∆NLS, mTDP-43 and GAPDH in rNLS8 SC before and after recovery compared to age-matched nTg control (cntrl) mice. There is no difference in the clearance of hTDP-43 or restoration of endogenous mouse TDP-43 between young and old animals. f Timeline of MN loss at L3–L5 levels of the SC in young (red) and aged (blue) rNLS8 mice showing that there is a precipitous decline in MN numbers while the transgene is expressed, which is completely halted by transgene suppression. Mean ± SD, n = 3–4 per time-point