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. 2023 Jul 18;120(30):e2217128120. doi: 10.1073/pnas.2217128120

Fig. 6.

Fig. 6.

Ssh1 elimination normalizes transcriptomic perturbations in tauP301S mice and activates the Nrf2 pathway. (A and B) Volcano plots of differentially expressed genes (DEGs) based on RNA-seq of transcripts in the cortex of 7-mo-old (A) P301S mice compared to WT mice and (B) P301S;Ssh1−/− mice compared to P301S mice. Log2 (fold change) is plotted against -Log10(P-value) with the dotted blue line representing nominal significance (≥1.3). Each circle represents one transcript, with red circles showing significant upregulation and green circles showing significant downregulation (n = 3 to 4 mice/genotype). (C and D) Of all common transcripts significantly altered in P301S mice relative to WT mice and in P301S;Ssh1−/− mice relative to P301S mice (165 transcripts), (C) butterfly line graph shows 160 transcripts normalize expression in the reverse direction in P301S;Ssh1−/− compared to P301S mice. (D) Spearman correlation analysis of Log2 fold changes of transcripts in P301S relative to WT mice and Log2 fold changes in P301S;Ssh1−/− relative to P301S mice shows a steep negative correlation (r = −0.932, P < 0.0001). (E) Qiagen® Ingenuity® pathway analysis (IPA) showing top canonical pathways increased in the cortex of P301S;Ssh1−/− mice compared to P301S mice, plotted by Z-score (blue bars) and -Log10(P-value) (red circles). Dotted blue line (≥2) = significant pathway activation Z-score. Dotted red line (≥1.3) = significant adjusted -Log10(P-value) for overlap of genes in each pathway. (F) IPA showing top canonical pathways decreased in the cortex of P301S;Ssh1−/− mice compared to P301S mice, plotted by negative Z-score (red bars) and -Log10(P-value) (blue circles). Dotted red line (≥2) = significant pathway activation Z-score. Dotted blue line (≥1.3) = significant adjusted -Log10(P-value) for overlap of genes in each pathway. (G) Representative blots of Nrf2 and Nrf2 targets (NQO1, GSTM1, & HMOX1) from cortical lysates of 7-mo-old WT, P301S, and P301S;Ssh1−/− mice. (H) Quantification of Nrf2, NQO1, GSTM1, and HMOX1 [one-way ANOVA; Nrf2: F (2, 18) = 4.645, P = 0.0236; NQO1: F (2, 17) = 6.763, P = 0.0069; GSTM1: F (2, 17) = 10.35, P = 0.0011; HMOX1: F (2, 18) = 0.2911, P = 0.7509; post hoc Dunnett, ***P = 0.0006, **P = 0.0037, *P < 0.05. n = 5 to 9 mice/genotype].