Elucidating mechanisms by which high levels of ATP prevent accumulation of aberrant protein aggregation

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K06654
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 44010:Cell biology-related
• Research Institution: Gunma University
• Principal Investigator: Takaine Masakatsu 群馬大学, 未来先端研究機構, 助教 (20573215)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: ATP / エネルギー代謝 / 酵母 / バイオセンサー / AMPK / アデニレートキナーゼ / 恒常性 / タンパク質凝集

Outline of Final Research Achievements

Cells use a chemical called adenosine triphosphate (ATP) as a controllable source of energy. Like a battery, each ATP contains a specific amount of energy that can be released when needed. Cells just need enough ATP to survive, but most cells store a lot more than they need. It is unclear why cells keep so much ATP, or whether this excess ATP has any other purpose.
To answer these questions, we identified mutants of the yeast Saccharomyces cerevisiae that had low levels of ATP and examined these cells. In S. cerevisiae cells with lower and changeable levels of ATP, proteins stick together, forming clumps. When they clump together, they stop working and can cause cells to die. Further experiments showed that reducing the levels of ATP just for a short time increased the rate at which proteins stick together.
Taken together, these results suggest that ATP plays a role in stopping proteins from sticking together, explaining why cells may store excess ATP, since it could aid survival.

Free Research Field

細胞生物学

Academic Significance and Societal Importance of the Research Achievements

本研究は細胞内ATP濃度が一過的にでも低下してしまうと、タンパク質の異常な凝集体形成を誘導する可能性があるため、細胞は常に高濃度のATPを保とうとする、というATPのエネルギー以外の役割を初めて示した。アルツハイマー病等の神経変性疾患を初めとした多くの疾患では、タンパク質の異常な凝集体が毒性を発揮して発症要因になる。本研究で示した、ATP恒常性の破綻による細胞内ATP濃度の変動は、これらのタンパク質凝集体が誘導する疾患の発症機序の一端を説明する可能性がある。このためATP恒常性の仕組みを追求することは、細胞内での異常なタンパク質凝集体形成を抑制する薬の開発に繋がると期待される。