Analysis of Danon disease using a human pathological model

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K17044
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Nara Medical University
• Principal Investigator: Iguchi Naohiko 奈良県立医科大学, 医学部附属病院, 研究員 (50838232)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: Danon病 / オートファジー / 神経変性疾患 / 脳オルガノイド

Outline of Final Research Achievements

In this study, we investigated the characteristics of brain organoids that could be considered for use as disease models. We generated brain organoids from human pluripotent stem cells and characterized their gene expression responses under hypoxic conditions of stress. We established a method to produce brain stem organoids, which are different from brain organoids that are considered to be models of the cerebral cortex, and clarified their characteristics. We found that a polypeptide produced from repeat sequences of the untranslated region of C9orf72, the causative gene of ALS, disrupts the phase-separation regulatory function of Kapβ2, a nuclear transport receptor. In addition, it is still unclear how LAMP-2, the causative gene of Danon disease, is involved in the autophagy disruption, and we studied LAMP-2 function through interaction analysis.

Free Research Field

神経内科学

Academic Significance and Societal Importance of the Research Achievements

本研究の成果から、神経筋疾患のモデルとなり得る脳オルガノイドについて、低酸素ストレス下での反応を検討し、また脳幹オルガノイドの作製法を樹立し、特性を明らかにした。今後の脳オルガノイドの神経筋疾患モデルとしての利用や、ストレス下での反応の検討を含めた病態解明、治療法の開発へ寄与することが期待される。