Aggregation of scaffolding protein DISC1 dysregulates phosphodiesterase 4 in Huntington’s disease
Motomasa Tanaka, … , Miles D. Houslay, Akira Sawa
Motomasa Tanaka, … , Miles D. Houslay, Akira Sawa
Published March 6, 2017
Citation Information: J Clin Invest. 2017;127(4):1438-1450. https://doi.org/10.1172/JCI85594.
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Research Article Cell biology Neuroscience

Aggregation of scaffolding protein DISC1 dysregulates phosphodiesterase 4 in Huntington’s disease

Abstract

Huntington’s disease (HD) is a polyglutamine (polyQ) disease caused by aberrant expansion of the polyQ tract in Huntingtin (HTT). While motor impairment mediated by polyQ-expanded HTT has been intensively studied, molecular mechanisms for nonmotor symptoms in HD, such as psychiatric manifestations, remain elusive. Here we have demonstrated that HTT forms a ternary protein complex with the scaffolding protein DISC1 and cAMP-degrading phosphodiesterase 4 (PDE4) to regulate PDE4 activity. We observed pathological cross-seeding between DISC1 and mutant HTT aggregates in the brains of HD patients as well as in a murine model that recapitulates the polyQ pathology of HD (R6/2 mice). In R6/2 mice, consequent reductions in soluble DISC1 led to dysregulation of DISC1-PDE4 complexes, aberrantly increasing the activity of PDE4. Importantly, exogenous expression of a modified DISC1, which binds to PDE4 but not mutant HTT, normalized PDE4 activity and ameliorated anhedonia in the R6/2 mice. We propose that cross-seeding of mutant HTT and DISC1 and the resultant changes in PDE4 activity may underlie the pathology of a specific subset of mental manifestations of HD, which may provide an insight into molecular signaling in mental illness in general.

Authors

Motomasa Tanaka, Koko Ishizuka, Yoko Nekooki-Machida, Ryo Endo, Noriko Takashima, Hideyuki Sasaki, Yusuke Komi, Amy Gathercole, Elaine Huston, Kazuhiro Ishii, Kelvin Kai-Wan Hui, Masaru Kurosawa, Sun-Hong Kim, Nobuyuki Nukina, Eiki Takimoto, Miles D. Houslay, Akira Sawa

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Figure 5

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

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Aberrantly enhanced PDE4 activity and reduced sucrose preference in R6/2...
(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.