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

1 Citation (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

ASJC Scopus subject areas

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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

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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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.",

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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

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