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

Tanaka, M. et al. (2017) Aggregation of scaffolding protein DISC1 dysregulates phosphodiesterase 4 in Huntington’s disease. Journal of Clinical Investigation, 127(4), pp. 1438-1450. (doi: 10.1172/JCI85594) (PMID:28263187)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Huston, Dr Elaine
• Authors: Tanaka, M., Ishizuka, K., Nekooki-Machida, Y., Endo, R., Takashima, N., Sasaki, H., Komi, Y., Gathercole, A., Huston, E., Ishii, K., Hui, K. K.-W., Kurosawa, M., Kim, S.-H., Nukina, N., Takimoto, E., Houslay, M. D., and Sawa, A.
• College/School: College of Medical Veterinary and Life Sciences > School of Life Sciences
• Journal Name: Journal of Clinical Investigation
• Publisher: Americal Society for Clinical Investigation
• ISSN: 0021-9738
• ISSN (Online): 1558-8238
• Published Online: 06 March 2017
• Copyright Holders: Copyright © 2017 The AuthorsAmerican Society for Clinical Investigation
• First Published: First published in Journal of Clinical Investigation 127(4):1438-1450
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher