TY - JOUR
T1 - A synthetic synaptic organizer protein restores glutamatergic neuronal circuits
AU - Suzuki, Kunimichi
AU - Elegheert, Jonathan
AU - Song, Inseon
AU - Sasakura, Hiroyuki
AU - Senkov, Oleg
AU - Matsuda, Keiko
AU - Kakegawa, Wataru
AU - Clayton, Amber J.
AU - Chang, Veronica T.
AU - Ferrer-Ferrer, Maura
AU - Miura, Eriko
AU - Kaushik, Rahul
AU - Ikeno, Masashi
AU - Morioka, Yuki
AU - Takeuchi, Yuka
AU - Shimada, Tatsuya
AU - Otsuka, Shintaro
AU - Stoyanov, Stoyan
AU - Watanabe, Masahiko
AU - Takeuchi, Kosei
AU - Dityatev, Alexander
AU - Radu Aricescu, A.
AU - Yuzaki, Michisuke
N1 - Funding Information:
We thank staff at the Diamond Light Source beamline I03; T. Walter and K. Harlos for support with protein crystallization; E. Budinger, O. Kobler, and J. Schneeberg for histology advice and assistance; and H. Sakuma and A. Sekigawa for the Airyscan super-resolution imaging. This work was funded by the Human Frontier Science Program (grant RGP0065/2014 to M.Y., A.D. and A.R.A.), the UK Medical Research Council (MRC; grants L009609 and MC_UP_1201/15 to A.R.A.), the Japan Society for the Promotion of Science (JSPS; grant 15H05772 and 16H06461 to M.Y.; 17K10949 and 1705584 to K.T.; 25893233, 26860148, 14J07587 and 18K19380 to K.S.; 18H04563 to W.K.; JP16H06280 to K.M. and K.S.), the Keio University Grant-in-Aid for Encouragement of Young Medical Scientists (to K.S.), the Keio Association Grant-in-Aid (to K.S.), the Astellas Foundation for Research on Metabolic Disorders (to K.S.), the Daiichi Sankyo Foundation of Life Science (to K.S.), the AMED (iD3 16nk0101302h0002 to K.T.; JP18dm0107124 to W.K.), the JST CREST (JPMJCR1854 to M.Y.), the JST ERATO (JPMJER1802 to W.K.), the Takeda Science Foundation (to M.Y. and W.K.), the Marie-Curie Actions postdoctoral fellowship (grant 328531 to J.E.), the University of Bordeaux Initiative of Excellence (IdEx) fellowship (to J.E.), the European Research Council (ERC Starting Grant 850820 SynLink to J.E.), the European Union 7th Framework Programme Initial Training Network (EU FP7 ITN; grant 606950 EXTRABRAIN to A.D.), and the Bundesministerium für Bildung und Forschung (BMBF; EnergI project, TP5, 01GQ1421A to A.D.).
Publisher Copyright:
Copyright © 2020 The Authors,
PY - 2020/8/28
Y1 - 2020/8/28
N2 - Neuronal synapses undergo structural and functional changes throughout life, which are essential for nervous system physiology. However, these changes may also perturb the excitatory–inhibitory neurotransmission balance and trigger neuropsychiatric and neurological disorders. Molecular tools to restore this balance are highly desirable. Here, we designed and characterized CPTX, a synthetic synaptic organizer combining structural elements from cerebellin-1 and neuronal pentraxin-1. CPTX can interact with presynaptic neurexins and postsynaptic AMPA-type ionotropic glutamate receptors and induced the formation of excitatory synapses both in vitro and in vivo. CPTX restored synaptic functions, motor coordination, spatial and contextual memories, and locomotion in mouse models for cerebellar ataxia, Alzheimer’s disease, and spinal cord injury, respectively. Thus, CPTX represents a prototype for structure-guided biologics that can efficiently repair or remodel neuronal circuits.
AB - Neuronal synapses undergo structural and functional changes throughout life, which are essential for nervous system physiology. However, these changes may also perturb the excitatory–inhibitory neurotransmission balance and trigger neuropsychiatric and neurological disorders. Molecular tools to restore this balance are highly desirable. Here, we designed and characterized CPTX, a synthetic synaptic organizer combining structural elements from cerebellin-1 and neuronal pentraxin-1. CPTX can interact with presynaptic neurexins and postsynaptic AMPA-type ionotropic glutamate receptors and induced the formation of excitatory synapses both in vitro and in vivo. CPTX restored synaptic functions, motor coordination, spatial and contextual memories, and locomotion in mouse models for cerebellar ataxia, Alzheimer’s disease, and spinal cord injury, respectively. Thus, CPTX represents a prototype for structure-guided biologics that can efficiently repair or remodel neuronal circuits.
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U2 - 10.1126/science.abb4853
DO - 10.1126/science.abb4853
M3 - Article
C2 - 32855309
AN - SCOPUS:85090003433
VL - 369
JO - Science
JF - Science
SN - 0036-8075
IS - 6507
M1 - eabb4853
ER -