論文 - 詳細
| RRC ID | 48884 |
|---|---|
| 著者 | 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. |
| タイトル | Aggregation of scaffolding protein DISC1 dysregulates phosphodiesterase 4 in Huntington's disease. |
| ジャーナル | 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. |
| 巻・号 | 127(4) |
| ページ | 1438-1450 |
| 公開日 | 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 |
| 引用数 | 16 |
| WOS 分野 | MEDICINE, RESEARCH & EXPERIMENTAL |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | News |
| 各媒体での言及数の合計 | 8 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 遺伝子材料 | CSII-CMV-MCS-IRES2-Venus (RDB04383) CSII-CMV-MCS (RDB04377) pCMV-VSV-G-RSV-Rev (RDB04393) pCAG-HIVgp (RDB04394). |