DYSREGULATION OF ENDOGENOUS TDP-43 IN CONDITIONAL TRANSGENIC MICE EXPRESSING HUMAN TDP-43 WITH MUTATED NUCLEAR LOCALIZATION SEQUENCE

IGAZ LM; KWONG LK; LEE EB; CHEN-PLOTKIN A; SWANSON E; UNGER TL; MALUNDA J; XU Y; WINTON MJ; TROJANOWSKI JQ; LEE VM

Indianapolis, IN

Conferencia; FTD 2010. The 7th International Conference on Frontotemporal Dementias; 2010

International Society for Frontotemporal Dementias (ISFTD)

Amyotrophic lateralsclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are characterizedby cytoplasmic protein aggregates in the brain and spinal cord that include TAR-DNA binding protein 43 (TDP-43). TDP-43 is normally localized in the nucleus with roles in the regulation of gene expression, and pathological cytoplasmic aggregates are associated with depletion of nuclear protein. Here, we generated transgenic mice expressing human TDP-43 with a defective nuclear localization signal in the forebrain (hTDP-43-ΔNLS),and compared them with mice expressing WT hTDP-43 (hTDP-43-WT) to determine the effects of mislocalized cytoplasmic TDP-43 on neuronal viability. Expression of either hTDP-43-ΔNLSor hTDP-43-WT led to neuron loss in selectively vulnerable forebrain regions,corticospinal tract degeneration, and motor spasticity recapitulating key aspects of FTLD and primary lateral sclerosis. Only rare cytoplasmic phosphorylated and ubiquitinated TDP-43 inclusions were seen in hTDP-43-ΔNLS mice, suggesting that cytoplasmic inclusions were not required to induce neuronal death. Instead,neurodegeneration in hTDP-43 and hTDP-43-ΔNLS expressing neurons was accompanied by a dramatic downregulation of the endogenous mouseTDP-43. Moreover, mice expressing hTDP-43-ΔNLSexhibited profound changes in gene expression in cortical neurons. Our data suggest that perturbation of endogenous nuclear TDP-43 results in loss of normal TDP-43 function(s) and gene regulatory pathways, culminating in degeneration of selectively vulnerable affected neurons.