RRC ID 48884
Author Tanaka M, Ishizuka K, Nekooki-Machida Y, Endo R, Takashima N, Sasaki H, Komi Y, Gathercole A, Huston E, Ishii K, Hui KK, Kurosawa M, Kim SH, Nukina N, Takimoto E, Houslay MD, Sawa A.
Title Aggregation of scaffolding protein DISC1 dysregulates phosphodiesterase 4 in Huntington's disease.
Journal J Clin Invest
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.
Volume 127(4)
Pages 1438-1450
Published 2017-4-3
DOI 10.1172/JCI85594
PII 85594
PMID 28263187
PMC PMC5373889
MeSH Animals Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism* Female HEK293 Cells Humans Huntingtin Protein / genetics Huntingtin Protein / metabolism Huntington Disease / enzymology* Mice, Transgenic Mutation Nerve Tissue Proteins / metabolism* Protein Aggregation, Pathological / enzymology*
IF 12.282
Times Cited 16
WOS Category MEDICINE, RESEARCH & EXPERIMENTAL
Resource
DNA material CSII-CMV-MCS-IRES2-Venus (RDB04383) CSII-CMV-MCS (RDB04377) pCMV-VSV-G-RSV-Rev (RDB04393) pCAG-HIVgp (RDB04394).