The role of the GON Domain on IP3R and calcium homeostasis

2023 Fiscal Year Final Research Report

• Project/Area Number: 17K18135
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Functional biochemistry; General physiology
• Research Institution: Tokyo Women's Medical University
• Principal Investigator: Yoshina Sawako 東京女子医科大学, 医学部, 講師 (00424672)
• Project Period (FY): 2017-04-01 – 2024-03-31
• Keywords: C.elegans / ADAMTS9 / カルシウム調節 / ミトコンドリア保護 / フェブキソスタット / 寿命

Outline of Final Research Achievements

Our research revealed that when ADAMTS9/GON-1 is deactivated, it triggers an unusual release of calcium ions from the endoplasmic reticulum (ER) through the IP3 receptor, leading to a rise in cytosolic calcium levels. Subsequently, we identified that directly interact with the GON domain. Furthermore, we searched for genes that suppress the above-mentioned phenotype and found ERAD-related factors. This suggests that the GON domain plays a crucial role in regulating the degradation of IP3 receptors.
There is a link between aging and mitochondrial function. We showed that FBX protects mitochondria and prevents age-related muscle deterioration in C. elegans. We used C. elegans as a model for Duchenne muscular dystrophy (DMD), Parkinson’s disease, and tauopathy. We demonstrated that FBX is a candidate drug for treating all these models.

Free Research Field

生理学

Academic Significance and Societal Importance of the Research Achievements

小胞体（ER）は蛋白質を合成・輸送し、多様な生命活動の基礎となる機能を担う細胞内小器官である。そのため、ER機能の破綻は、蛋白質輸送の阻害に加え、代謝や脂質合成などを変化させ、結果的に種々な疾患を引き起こす。ADAMTS9の細胞内機能を明らかにし、蛋白質輸送の恒常性を保つメカニズムと、を解明することにより、広い生命科学分野の理解と、病態の解明につながることが期待される。