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 |
11.864
|
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). |