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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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 4

The amount of DISC1-PDE4 complex was reduced by decreased soluble DISC1 levels in R6/2 mice.

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The amount of DISC1-PDE4 complex was reduced by decreased soluble DISC1 ...
(A) Soluble DISC1 but not soluble PDE4B levels in supernatant fractions (Sup) were reduced in cerebral cortex (top) and striatum (bottom) from 12-week-old R6/2 mice, compared with those from WT mice. Total DISC1 and PDE4B levels in total homogenates (Total) were not changed between WT and R6/2 mice. β-Actin is a loading control. An m317C anti-DISC1 antibody was used to detect DISC1, and a negative control with rabbit secondary antibody alone is also shown. Data represent mean + SEM. **P < 0.01, ***P < 0.001; unpaired 2-tailed t test. n = 3 per group. (B) The amount of DISC1-PDE4B complex in 12-week-old R6/2 mouse brains was decreased compared with that in WT brains. Immunoprecipitation was performed by an anti–pan-PDE4B antibody, followed by immunoblotting with anti-DISC1 antibody (D27). GAPDH is a loading control and used for normalization of the IP data. Data represent mean + SEM. **P < 0.01; unpaired 2-tailed t test. n = 5 per group. (C) Exogenous addition of HTT513Q82, but not HTT513Q18, significantly reduced DISC1-PDE4B interactions in HEK293T cells. Lysates of the cells overexpressing GFP alone (–), HTT513Q18-GFP (Q18), or HTT513Q82-GFP (Q82) were added to lysates of the cells overexpressing DISC1-Myc and PDE4B1-HA. Mixtures were processed for immunoprecipitation with an anti–c-Myc antibody, followed by immunoblotting. Data represent mean + SEM (3 independent sample sets). *P < 0.05, **P < 0.01; unpaired 2-tailed t test.