Fig. 3: ISR activation from in vivo model of ALS-associated TDP-43 pathology is corrected by acute dosing of eIF2B activator, DN9058. | Nature Communications

Fig. 3: ISR activation from in vivo model of ALS-associated TDP-43 pathology is corrected by acute dosing of eIF2B activator, DN9058.

From: Investigational eIF2B activator DNL343 modulates the integrated stress response in preclinical models of TDP-43 pathology and individuals with ALS in a randomized clinical trial

Fig. 3

a Experimental design of acute DN9058 dosing of rNLS8 transgenic mice. All animals were fed Dox-containing diet until 8 weeks of age, including non-transgenic (nTg) controls, single transgenic (sTg) controls and double transgenic (rNLS8) mice, then Dox was removed from their diet except for group 6 (double transgenic (rNLS8) on Dox for two additional weeks). On 13th and 14th day off Dox, indicated groups were dosed with DN9058 by oral gavage at 50 mg/kg per animal weight. b-c Quantification of p-eIF2α normalized to loading control eIF2α (b) and ATF4 level normalized to GAPDH (c) from Supplementary Fig. 4i and j (n = 8 sTg Control or 12 rNLS8 mice). Data are shown as fold-changes relative to vehicle-treated control mice. d Transcriptional fold change of pre-selected ISR genes in rostral cortex of indicated mouse line (n = 7 (nTg Ctrl), 8 (rNLS8 Dox), 9 (sTg Ctrl) and 12 (rNLS8) mice). Data are shown as mean ± SEM (b−d). Statistical significance was determined with Kruskal-Wallis test with Dunn’s multiple comparisons (b), ordinary One-way ANOVA with Tukey’s multiple comparison (c, d). Source data are provided in Source Data file.

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