2021 Fiscal Year Final Research Report
Dysfunction of ERAP1 induces anxiety disorder via excess serotonin synthesis
Project/Area Number |
19K07405
|
Research Category |
Grant-in-Aid for Scientific Research (C)
|
Allocation Type | Multi-year Fund |
Section | 一般 |
Review Section |
Basic Section 49010:Pathological biochemistry-related
|
Research Institution | Teikyo Heisei University |
Principal Investigator |
|
Project Period (FY) |
2019-04-01 – 2022-03-31
|
Keywords | アミノペプチダーゼ / 不安障害 / セロトニン / セロトニン神経 / TPH2 |
Outline of Final Research Achievements |
Reduction of enzymatic activity of ERAP1 promotes anxious behaviors. In this study, we elucidated the mechanisms promoting anxious behavior associated with ERAP1 gene deletion. We found that loss of ERAP1 enzyme activity in the raphe nucleus of the brain promotes excessive serotonin synthesis by suppressing the expression of the tryptophan hydroxylase 2-transcriptional repressor, REST. We also showed that the stress behavior elicited by ERAP1 gene deficiency is due to excess serotonin. Thus, ERAP1 is one of the regulators of serotonin synthesis in the brain and dysfunction of ERAP1 can induce anxiety disorders.
|
Free Research Field |
生化学
|
Academic Significance and Societal Importance of the Research Achievements |
これまでにERAP1の高次機能への関与を示唆する知見はなく、現段階で本酵素が精神障害の原因遺伝子となるとの報告はない。ERAP1遺伝子上の一塩基多型の中に酵素活性を70%程度低下させるものが存在することが分かっている。この遺伝子変異のマイナーアリル頻度は、人種問わず>0.4であることから、ERAP1が不安障害の原因遺伝子である可能性が高い。本成果を契機として不安障害の発症機会が理解できれば、明確な線引きの難しい不安障害と類似精神障害間の誤診を防ぐ一助となり得る。
|