A synthetic synaptic organizer protein restores glutamatergic neuronal circuits

Kunimichi Suzuki; Jonathan Elegheert; Inseon Song; Hiroyuki Sasakura; Oleg Senkov; Keiko Matsuda; Wataru Kakegawa; Amber J. Clayton; Veronica T. Chang; Maura Ferrer-Ferrer; Eriko Miura; Rahul Kaushik; Masashi Ikeno; Yuki Morioka; Yuka Takeuchi; Tatsuya Shimada; Shintaro Otsuka; Stoyan Stoyanov; Masahiko Watanabe; Kosei Takeuchi; Alexander Dityatev; A. Radu Aricescu; Michisuke Yuzaki

doi:10.1126/science.abb4853

A synthetic synaptic organizer protein restores glutamatergic neuronal circuits

Kunimichi Suzuki, Jonathan Elegheert, Inseon Song, Hiroyuki Sasakura, Oleg Senkov, Keiko Matsuda, Wataru Kakegawa, Amber J. Clayton, Veronica T. Chang, Maura Ferrer-Ferrer, Eriko Miura, Rahul Kaushik, Masashi Ikeno, Yuki Morioka, Yuka Takeuchi, Tatsuya Shimada, Shintaro Otsuka, Stoyan Stoyanov, Masahiko Watanabe, Kosei TakeuchiAlexander Dityatev, A. Radu Aricescu, Michisuke Yuzaki

Department of Physiology

Research output: Contribution to journal › Article › peer-review

4 Citations (Scopus)

Abstract

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.

Original language	English
Article number	eabb4853
Journal	Science
Volume	369
Issue number	6507
DOIs	https://doi.org/10.1126/science.abb4853
Publication status	Published - 2020 Aug 28

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Suzuki, K., Elegheert, J., Song, I., Sasakura, H., Senkov, O., Matsuda, K., Kakegawa, W., Clayton, A. J., Chang, V. T., Ferrer-Ferrer, M., Miura, E., Kaushik, R., Ikeno, M., Morioka, Y., Takeuchi, Y., Shimada, T., Otsuka, S., Stoyanov, S., Watanabe, M., ... Yuzaki, M. (2020). A synthetic synaptic organizer protein restores glutamatergic neuronal circuits. Science, 369(6507), [eabb4853]. https://doi.org/10.1126/science.abb4853

A synthetic synaptic organizer protein restores glutamatergic neuronal circuits. / Suzuki, Kunimichi; Elegheert, Jonathan; Song, Inseon; Sasakura, Hiroyuki; Senkov, Oleg; Matsuda, Keiko ; Kakegawa, Wataru; Clayton, Amber J.; Chang, Veronica T.; Ferrer-Ferrer, Maura; Miura, Eriko; Kaushik, Rahul; Ikeno, Masashi; Morioka, Yuki; Takeuchi, Yuka; Shimada, Tatsuya; Otsuka, Shintaro; Stoyanov, Stoyan; Watanabe, Masahiko; Takeuchi, Kosei; Dityatev, Alexander; Radu Aricescu, A.; Yuzaki, Michisuke.

In: Science, Vol. 369, No. 6507, eabb4853, 28.08.2020.

Research output: Contribution to journal › Article › peer-review

Suzuki, K, Elegheert, J, Song, I, Sasakura, H, Senkov, O, Matsuda, K , Kakegawa, W, Clayton, AJ, Chang, VT, Ferrer-Ferrer, M, Miura, E, Kaushik, R, Ikeno, M, Morioka, Y, Takeuchi, Y, Shimada, T, Otsuka, S, Stoyanov, S, Watanabe, M, Takeuchi, K, Dityatev, A, Radu Aricescu, A & Yuzaki, M 2020, 'A synthetic synaptic organizer protein restores glutamatergic neuronal circuits', Science, vol. 369, no. 6507, eabb4853. https://doi.org/10.1126/science.abb4853

Suzuki, Kunimichi ; Elegheert, Jonathan ; Song, Inseon ; Sasakura, Hiroyuki ; Senkov, Oleg ; Matsuda, Keiko ; Kakegawa, Wataru ; Clayton, Amber J. ; Chang, Veronica T. ; Ferrer-Ferrer, Maura ; Miura, Eriko ; Kaushik, Rahul ; Ikeno, Masashi ; Morioka, Yuki ; Takeuchi, Yuka ; Shimada, Tatsuya ; Otsuka, Shintaro ; Stoyanov, Stoyan ; Watanabe, Masahiko ; Takeuchi, Kosei ; Dityatev, Alexander ; Radu Aricescu, A. ; Yuzaki, Michisuke. / A synthetic synaptic organizer protein restores glutamatergic neuronal circuits. In: Science. 2020 ; Vol. 369, No. 6507.

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title = "A synthetic synaptic organizer protein restores glutamatergic neuronal circuits",

abstract = "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{\textquoteright}s disease, and spinal cord injury, respectively. Thus, CPTX represents a prototype for structure-guided biologics that can efficiently repair or remodel neuronal circuits.",

author = "Kunimichi Suzuki and Jonathan Elegheert and Inseon Song and Hiroyuki Sasakura and Oleg Senkov and Keiko Matsuda and Wataru Kakegawa and Clayton, {Amber J.} and Chang, {Veronica T.} and Maura Ferrer-Ferrer and Eriko Miura and Rahul Kaushik and Masashi Ikeno and Yuki Morioka and Yuka Takeuchi and Tatsuya Shimada and Shintaro Otsuka and Stoyan Stoyanov and Masahiko Watanabe and Kosei Takeuchi and Alexander Dityatev and {Radu Aricescu}, A. and Michisuke Yuzaki",

note = "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 f?r Bildung und Forschung (BMBF; EnergI project, TP5, 01GQ1421A to A.D.).",

year = "2020",

month = aug,

day = "28",

doi = "10.1126/science.abb4853",

language = "English",

volume = "369",

journal = "Science",

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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 f?r Bildung und Forschung (BMBF; EnergI project, TP5, 01GQ1421A to A.D.).

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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A synthetic synaptic organizer protein restores glutamatergic neuronal circuits

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