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A synthetic synaptic organizer protein restores glutamatergic neuronal circuits

DOI: 10.1126/science.abb4853 DOI Help

Authors: Kunimichi Suzuki (Keio University School of Medicine) , Jonathan Elegheert (University of Oxford) , Inseon Song (German Center for Neurodegenerative Diseases (DZNE)) , Hiroyuki Sasakura (Aichi Medical University) , Oleg Senkov (German Center for Neurodegenerative Diseases (DZNE)) , Keiko Matsuda (Keio University School of Medicine) , Wataru Kakegawa (Keio University School of Medicine) , Veronica T. Chang (University of Oxford; MRC Laboratory of Molecular Biology) , Maura Ferrer-ferrer (German Center for Neurodegenerative Diseases (DZNE)) , Eriko Miura (Keio University School of Medicine) , Rahul Kaushik (German Center for Neurodegenerative Diseases (DZNE); Center for Behavioral Brain Sciences (CBBS)) , Masashi Ikeno (Aichi Medical University) , Yuki Morioka (Aichi Medical University) , Yuka Takeuchi (Aichi Medical University) , Tatsuya Shimada (Keio University School of Medicine) , Shintaro Otsuka (Keio University School of Medicine) , Stoyan Stoyanov (German Center for Neurodegenerative Diseases (DZNE)) , Masahiko Watanabe (Hokkaido University Graduate School of Medicine) , Kosei Takeuchi (Aichi Medical University) , Alexander Dityatev (German Center for Neurodegenerative Diseases (DZNE); Center for Behavioral Brain Sciences (CBBS); Otto von Guericke University) , A. Radu Aricescu (University of Oxford; MRC Laboratory of Molecular Biology) , Michisuke Yuzaki (Keio University School of Medicine)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Science

State: Published (Approved)
Published: August 2020

Open Access Open Access

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.

Subject Areas: Biology and Bio-materials

Instruments: I03-Macromolecular Crystallography