| First Author | Tanaka M | Year | 2017 |
| Journal | J Clin Invest | Volume | 127 |
| Issue | 4 | Pages | 1438-1450 |
| PubMed ID | 28263187 | Mgi Jnum | J:243373 |
| Mgi Id | MGI:5908313 | Doi | 10.1172/JCI85594 |
| Citation | Tanaka M, et al. (2017) Aggregation of scaffolding protein DISC1 dysregulates phosphodiesterase 4 in Huntington's disease. J Clin Invest 127(4):1438-1450 |
| abstractText | 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. |
