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

• Published in: The Journal of clinical investigation Vol. 127; no. 4; pp. 1438 - 1450
• Main Authors: Tanaka, Motomasa, Ishizuka, Koko, Nekooki-Machida, Yoko, Endo, Ryo, Takashima, Noriko, Sasaki, Hideyuki, Komi, Yusuke, Gathercole, Amy, Huston, Elaine, Ishii, Kazuhiro, Hui, Kelvin Kai-Wan, Kurosawa, Masaru, Kim, Sun-Hong, Nukina, Nobuyuki, Takimoto, Eiki, Houslay, Miles D., Sawa, Akira
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.04.2017
• Subjects: Animals; Behavior; Biomedical research; Brain research; Care and treatment; Cellular proteins; Cyclic Nucleotide Phosphodiesterases, Type 4 - metabolism; Development and progression; Experiments; Female; Gene expression; Genetic aspects; Health aspects; HEK293 Cells; Humans; Huntingtin Protein - genetics; Huntingtin Protein - metabolism; Huntington Disease - enzymology; Huntington's disease; Huntingtons disease; Mice, Transgenic; Mutation; Nerve Tissue Proteins - metabolism; Pathology; Phosphodiesterases; Protein Aggregation, Pathological - enzymology; Proteins; Scientists; Studies
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI85594

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.