2022 Fiscal Year Final Research Report

Removal of translation repression of tryptophan hydroxylase 2 and drug discovery by exon skipping strategy

Research Project

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Project/Area Number	19K22581
Research Category	Grant-in-Aid for Challenging Research (Exploratory)
Allocation Type	Multi-year Fund
Review Section	Medium-sized Section 51:Brain sciences and related fields
Research Institution	St. Marianna University School of Medicine
Principal Investigator	Hiroi Tomoko 聖マリアンナ医科大学, 医学研究科, 講師 (20238398)
Co-Investigator(Kenkyū-buntansha)	那和雪乃聖マリアンナ医科大学, 医学研究科, 助教 (10549786) 大滝正訓聖マリアンナ医科大学, 医学部, 助教 (20612683)
Project Period (FY)	2019-06-28 – 2023-03-31
Keywords	エクソン・スキップ / 翻訳抑制
Outline of Final Research Achievements	Tryptophan hydroxylase 2 (TPH2) is the rate-limiting enzyme in serotonin (5-HT) synthesis in the brain. Previous studies have shown that the human TPH2 (hTPH2) exon 2 contains a translational auto-repression domain. During this project, we initially attempted to increase the hTPH2 protein levels by skipping of the hTPH2 exon 2. Contrary to our expectation, skipping of the hTPH2 exon 2 did not increase the hTPH2 levels. Instead, in-depth analysis of regulatory effects of the hTPH2 exon 3 on the hTPH2 translation revealed that the hTPH2 exon 3 contains a previously unappreciated potent translational auto-repression element (TRE). The hTPH2 exon 3 TRE inhibited the hTPH2 translation in a nucleotide sequence-dependent, but an encoded amino acid sequence-independent manner. The hTPH2 exon 3 TRE did not affect the hTPH2 transcription levels, and only repressed the hTPH2 translation when localized within the hTPH2 protein-coding region.
Free Research Field	分子生物学
Academic Significance and Societal Importance of the Research Achievements	セロトニン作動性神経系の機能障害は、不安障害、気分障害など様々な疾患の原因となる。中枢型トリプトファン水酸化酵素(TPH2)は重要な創薬標的であるが、その転写制御機構は極めて複雑であり、未だTPH2発現量を増加させるための画期的な方法は見出されていない。今回見出された［翻訳領域に存在する翻訳抑制塩基配列］は、これまでの転写制御解明のための研究において、発現量が増加する結果を鮮明に得られなかった原因のひとつであると考えられる。これは今後の研究を進める上で重要な発見であり、転写制御機構の解明と並行して、この翻訳抑制機構を解明することが、TPH2発現量を増加させるために必須となろう。