RNA-binding proteins that regulate microglial genes associated with neurological diseases

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K07982
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Meiji Pharmaceutical University
• Principal Investigator: Kino Yoshihiro 明治薬科大学, 薬学部, 教授 (80415140)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: RNA結合タンパク質 / アルツハイマー病 / スプライシング / hnRNPAファミリー / CD33 / TREM2

Outline of Final Research Achievements

Microglial cells are brain cells implicated in the pathomechanisms of neurological disorders, including Alzheimer’s disease (AD). Many genes that are preferentially expressed in microglia have been identified as the genetic risk of AD. Some of these genes have essential roles in the functions of microglia. In this study, we attempted to reveal the regulation of these genes at the level of RNA metabolisms. Previously, we reported that exon 3 of TREM2 is alternatively spliced. Here, we identified the RNA-binding protein CELF2 as a regulator of exon 3 splicing. In addition, we revealed that translation of TREM2 is regulated through its 5’ untranslated region. Importantly, both exon 3 splicing and translational regulation of TREM2 are specific to primates. We also focused on the splicing regulation of CD33, in which exon 2 splicing is associated with the risk of AD. We found that HNRNPA family proteins suppress exon 2 inclusion, promoting the production of a protective isoform of CD33.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

本研究ではミクログリアの機能に関わるタンパク質であるTREM2とCD33がどのような発現制御を受けているかを明らかにした。この制御機構の知見を応用することで、両タンパク質の発現の人工的な操作が可能であると考えられる。TREM2やCD33はアルツハイマー病に影響するため、新たな治療介入の道が拓かれる。また、今回、ヒトとマウスのTREM2を比較したが、制御の受け方には種間で差がみられた。疾患研究ではマウスが多用されるが、少なくとも一部の性質はマウスのTREM2では再現されなかった。マウスモデルの使用は有用であるが、ミクログリアの動態の解釈には注意が必要であることを示唆する結果となった。