Fig. 6: TDP-43 pathology causes early activation of the ISR and apoptosis signaling in rNLS8 mice. | Molecular Psychiatry

Fig. 6: TDP-43 pathology causes early activation of the ISR and apoptosis signaling in rNLS8 mice.

From: Early activation of cellular stress and death pathways caused by cytoplasmic TDP-43 in the rNLS8 mouse model of ALS and FTD

Fig. 6

A Summary of gene expression changes in the cortex of rNLS8 mice over time. B Mechanism schema. TDP-43 mislocalisation induces early activation of multiple cell stress signaling pathways in the cortex of rNLS8 mice even before disease onset, such as the ISR, UPR, DNA damage response, and apoptosis. Notably, the prolonged activation of these cell stress pathways caused by TDP-43 pathology, in particular the ISR, continues through early-disease stages where rNLS8 mice displayed dramatic elevation of p-eIF2α and ATF4 protein, and impairment of cellular metabolism. Dysregulation of stress pathways leads to reduction of anti-apoptotic Bcl2, continued increased expression of pro-apoptotic genes (Bid, Bim, Noxa, and Puma), and increases of cleaved caspase-3 and astrogliosis, likely contributing to neurodegeneration in rNLS8 mice.

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