ATP-dependent coupling of pre- and post-synaptic organelles movements at central synapses and its implication in synaptic plasticity and transmission

2021 Fiscal Year Final Research Report

• Project/Area Number: 18K06494
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 46010:Neuroscience-general-related
• Research Institution: Okinawa Institute of Science and Technology Graduate University
• Principal Investigator: Guillaud Laurent 沖縄科学技術大学院大学, 分子神経科学ユニット, グループリーダー (90596222)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Keywords: liquid phase separation / ATP / synapse / neurodegeneration

Outline of Final Research Achievements

Here, I present compelling evidences showing that intracellular concentration ATP produced by active mitochondria in mouse and human neurons is pivotal to maintain the presynaptic release machinery and axonal proteins solubility via liquid phase separation (LPS). Fluorescence recovery after photobleaching experiments demonstrate that decrease in intracellular ATP after mitochondria inhibition, leads to condensation of axo-terminal cytosol, synaptic vesicles, and active zone components and control the functional organization of mouse calyceal synapses. In vitro experiments on purified proteins involved in PD, AD and ALS show they all undergo ATP concentration-dependent LPS at different ATP concentration. Human iPSC-derived neurons from PD and ALS patients show consistent reduction in axonal cytosol fluid phase correlated with significant reduction in intracellular ATP.

Free Research Field

Neuroscience

Academic Significance and Societal Importance of the Research Achievements

Future research to improve mitochondria activity and ATP production might contribute to the development of novel therapeutics to prevent or alleviate protein aggregation before the apparition of severe synaptic defects and pathological symptoms in PD, AD or ALS.