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. 2017 Mar 6;127(4):1438–1450. doi: 10.1172/JCI85594

Figure 5. Aberrantly enhanced PDE4 activity and reduced sucrose preference in R6/2 mice are recovered by exogenous DISC1 expression.

Figure 5

(A) The 25-mer peptides #40–#42 (residues 194–228 for mouse DISC1 [left], residues 196–230 for human DISC1 [right]) in DISC1 showed binding to maltose-binding protein (MBP)–HTT513Q18 (bottom) but not MBP alone (top) on peptide array. A black line corresponds to the core region of aggregates, which was identified by limited proteolysis and mass spectrometry (see Figure 3C). Representative data are shown from 3 and 2 independent samples for mouse and human DISC1, respectively. (B) Aberrant augmentation of PDE4 activity in striatum of R6/2 mice was normalized with WT or Δ201-228-DISC1. Data represent mean + SEM. *P < 0.05, **P < 0.01; 1-way ANOVA followed by Bonferroni post hoc corrections. n = 6, 3, 3, and 3 for WT, R6/2 + Control, R6/2 + WT-DISC1, and R6/2 + Δ201-228-DISC1 mice, respectively. (C) The number of cells with EM48-positive HTT aggregates was not affected by expression of Δ201-228-nDISC1 in striatum of mice at 12 weeks. Data represent mean + SEM. Unpaired 2-tailed t test was used for statistical analysis. n = 3 per group. (D) The number of NeuN-positive neurons was not affected by expression of Δ201-228-nDISC1 in striatum of mice at 12 weeks. Data represent mean + SEM. *P < 0.05, ***P < 0.001; 1-way ANOVA followed by Bonferroni post hoc corrections. n = 4, 4, 6, and 5 for WT + EGFP, WT + Δ201-228-nDISC1, R6/2 + EGFP, and R6/2 + Δ201-228-nDISC1 mice, respectively. (E) The impairment of motor function of R6/2 mice was not rescued by expression of Δ201-228-nDISC1. The latency to fall off the rotarod was examined in mice at 9 weeks. Data represent mean ± SEM. ***P < 0.001; 1-way ANOVA followed by Bonferroni post hoc corrections. n = 17, 16, 8, and 8 for WT + EGFP, WT + Δ201-228-nDISC1, R6/2 + EGFP, and R6/2 + Δ201-228-nDISC1 mice, respectively. (F) Reduced sucrose preference in R6/2 mice was rescued by expression of Δ201-228-nDISC1. The sucrose intake was measured in mice at 9 weeks. Data represent mean + SEM. ***P < 0.001; 1-way ANOVA followed by Bonferroni post hoc corrections. n = 17, 16, 17, and 20 mice for WT + EGFP, WT + Δ201-228-nDISC1, R6/2 + EGFP, and R6/2 + Δ201-228-nDISC1 mice, respectively.