Heparan Sulfate Organizes Neuronal Synapses through Neurexin Partnerships.

Autor:	Zhang P; Djavad Mowafaghian Centre for Brain Health and Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada. Electronic address: peng.pengzhang@gmail.com., Lu H; Djavad Mowafaghian Centre for Brain Health and Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada., Peixoto RT; Howard Hughes Medical Institute, Harvard Medical School, Department of Neurobiology, Boston, MA 02115, USA; Istituto Italiano di Tecnologia, Genova 16163, Italy., Pines MK; Department of Zoology and Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada., Ge Y; Djavad Mowafaghian Centre for Brain Health and Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada., Oku S; Djavad Mowafaghian Centre for Brain Health and Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada., Siddiqui TJ; Djavad Mowafaghian Centre for Brain Health and Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada., Xie Y; Djavad Mowafaghian Centre for Brain Health and Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada., Wu W; Djavad Mowafaghian Centre for Brain Health and Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada; Medical School, Henan University of Science and Technology, Luoyang 471023, China., Archer-Hartmann S; Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, USA., Yoshida K; Department of Neuropsychiatry, Keio University School of Medicine, Tokyo 160-8582, Japan., Tanaka KF; Department of Neuropsychiatry, Keio University School of Medicine, Tokyo 160-8582, Japan., Aricescu AR; MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK., Azadi P; Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, USA., Gordon MD; Department of Zoology and Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada., Sabatini BL; Howard Hughes Medical Institute, Harvard Medical School, Department of Neurobiology, Boston, MA 02115, USA., Wong ROL; Department of Biological Structure, University of Washington, Seattle, WA 98195, USA., Craig AM; Djavad Mowafaghian Centre for Brain Health and Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada. Electronic address: acraig@mail.ubc.ca.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2018 Sep 06; Vol. 174 (6), pp. 1450-1464.e23. Date of Electronic Publication: 2018 Aug 09.
DOI:	10.1016/j.cell.2018.07.002
Abstrakt:	Synapses are fundamental units of communication in the brain. The prototypical synapse-organizing complex neurexin-neuroligin mediates synapse development and function and is central to a shared genetic risk pathway in autism and schizophrenia. Neurexin's role in synapse development is thought to be mediated purely by its protein domains, but we reveal a requirement for a rare glycan modification. Mice lacking heparan sulfate (HS) on neurexin-1 show reduced survival, as well as structural and functional deficits at central synapses. HS directly binds postsynaptic partners neuroligins and LRRTMs, revealing a dual binding mode involving intrinsic glycan and protein domains for canonical synapse-organizing complexes. Neurexin HS chains also bind novel ligands, potentially expanding the neurexin interactome to hundreds of HS-binding proteins. Because HS structure is heterogeneous, our findings indicate an additional dimension to neurexin diversity, provide a molecular basis for fine-tuning synaptic function, and open therapeutic directions targeting glycan-binding motifs critical for brain development. (Copyright © 2018 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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