한빛사논문
Eunji Cho1,5, Sang-Eun Lee1,2,5, Unghwi Lee1, Yuna Goh1, Seonyoung Jeong1, Junyoung Choi3, Won-Ki Jeong4 and Sunghoe Chang1
1Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, South Korea.
2UK Dementia Research Institute, University College London, Gower St, London WC1E 6BT, UK.
3School of Electrical and Computer Engineering, Ulsan National Institute of Science and Technology, Ulsan 44919, South Korea.
4Department of Computer Science and Engineering, Korea University, Seoul 02841, South Korea.
5These authors contributed equally: Eunji Cho, Sang-Eun Lee.
Corresponding author: Correspondence to Sunghoe Chang
Abstract
nArgBP2, a candidate gene for intellectual disability, is a postsynaptic protein critical for dendritic spine development and morphogenesis, and its knockdown (KD) in developing neurons severely impairs spine-bearing excitatory synapse formation. Surprisingly, nArgBP2 KD in mature neurons did not cause morphological defects in the existing spines at rest, raising questions of how it functions in mature neurons. We found that unlike its inaction at rest, nArgBP2 KD completely inhibited the enlargement of dendritic spines during chemically induced long-term potentiation (cLTP) in mature neurons. We further found that nArgBP2 forms condensates in dendritic spines and that these condensates are dispersed by cLTP, which spatiotemporally coincides with spine head enlargement. Condensates with CaMKII phosphorylation-deficient mutant or CaMKII inhibition are neither dispersed nor accompanied by spine enlargement during cLTP. We found that nArgBP2 condensates in spines exhibited liquid-like properties, and in heterologous and in vitro expression systems, nArgBP2 undergoes liquid-liquid phase separation via multivalent intermolecular interactions between SH3 domains and proline-rich domains. It also forms coacervates with CaMKIIα, which is rapidly dissembled by calcium/CaMKIIα-dependent phosphorylation. We further showed that the interaction between nArgBP2 and WAVE1 competes with nArgBP2 phase separation and that blocking the nArgBP2-WAVE1 interaction prevents spine enlargement during cLTP. Together, our results suggest that nArgBP2 at rest is confined to the condensates but is released by CaMKIIα-mediated phosphorylation during synaptic plasticity, which regulates its timely interaction with WAVE1 to induce spine head enlargement in mature neurons.
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