PMID- 36599935
OWN - NLM
STAT- MEDLINE
DCOM- 20230207
LR  - 20230217
IS  - 2092-6413 (Electronic)
IS  - 1226-3613 (Print)
IS  - 1226-3613 (Linking)
VI  - 55
IP  - 1
DP  - 2023 Jan
TI  - Biomolecular condensate assembly of nArgBP2 tunes its functionality to manifest 
      the structural plasticity of dendritic spines.
PG  - 108-119
LID - 10.1038/s12276-022-00918-6 [doi]
AB  - 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 CaMKIIalpha, which is rapidly dissembled by 
      calcium/CaMKIIalpha-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 CaMKIIalpha-mediated phosphorylation during synaptic plasticity, 
      which regulates its timely interaction with WAVE1 to induce spine head 
      enlargement in mature neurons.
CI  - (c) 2023. The Author(s).
FAU - Cho, Eunji
AU  - Cho E
AUID- ORCID: 0000-0002-8486-3641
AD  - Department of Physiology and Biomedical Sciences, Seoul National University 
      College of Medicine, Seoul, 03080, South Korea.
FAU - Lee, Sang-Eun
AU  - Lee SE
AUID- ORCID: 0000-0001-7371-8556
AD  - Department of Physiology and Biomedical Sciences, Seoul National University 
      College of Medicine, Seoul, 03080, South Korea.
AD  - UK Dementia Research Institute, University College London, Gower St, London, WC1E 
      6BT, UK.
FAU - Lee, Unghwi
AU  - Lee U
AD  - Department of Physiology and Biomedical Sciences, Seoul National University 
      College of Medicine, Seoul, 03080, South Korea.
FAU - Goh, Yuna
AU  - Goh Y
AD  - Department of Physiology and Biomedical Sciences, Seoul National University 
      College of Medicine, Seoul, 03080, South Korea.
FAU - Jeong, Seonyoung
AU  - Jeong S
AD  - Department of Physiology and Biomedical Sciences, Seoul National University 
      College of Medicine, Seoul, 03080, South Korea.
FAU - Choi, Junyoung
AU  - Choi J
AD  - School of Electrical and Computer Engineering, Ulsan National Institute of 
      Science and Technology, Ulsan, 44919, South Korea.
FAU - Jeong, Won-Ki
AU  - Jeong WK
AD  - Department of Computer Science and Engineering, Korea University, Seoul, 02841, 
      South Korea.
FAU - Chang, Sunghoe
AU  - Chang S
AUID- ORCID: 0000-0002-3446-7288
AD  - Department of Physiology and Biomedical Sciences, Seoul National University 
      College of Medicine, Seoul, 03080, South Korea. sunghoe@snu.ac.kr.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230104
PL  - United States
TA  - Exp Mol Med
JT  - Experimental & molecular medicine
JID - 9607880
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2)
SB  - IM
MH  - *Dendritic Spines/metabolism
MH  - *Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics/metabolism
MH  - Biomolecular Condensates
MH  - Neuronal Plasticity/physiology
MH  - Long-Term Potentiation/physiology
MH  - Synapses/metabolism
MH  - Hippocampus/metabolism
PMC - PMC9898538
COIS- The authors declare no competing interests.
EDAT- 2023/01/05 06:00
MHDA- 2023/02/08 06:00
PMCR- 2023/01/04
CRDT- 2023/01/04 23:18
PHST- 2022/07/20 00:00 [received]
PHST- 2022/11/09 00:00 [accepted]
PHST- 2022/11/07 00:00 [revised]
PHST- 2023/01/05 06:00 [pubmed]
PHST- 2023/02/08 06:00 [medline]
PHST- 2023/01/04 23:18 [entrez]
PHST- 2023/01/04 00:00 [pmc-release]
AID - 10.1038/s12276-022-00918-6 [pii]
AID - 918 [pii]
AID - 10.1038/s12276-022-00918-6 [doi]
PST - ppublish
SO  - Exp Mol Med. 2023 Jan;55(1):108-119. doi: 10.1038/s12276-022-00918-6. Epub 2023 
      Jan 4.