Zhang, P., Lu, H., Peixoto, R.T., Pines, M.K., Ge, Y., Oku, S., Siddiqui, T.J., Xie, Y., Wu, W., Archer-Hartmann, S., Yoshida, K., Tanaka, K.F., Aricescu, A.R., Azadi, P., Gordon, M.D., Sabatini, B.L., Wong, R.O.L., Craig, A.M. (2018). Heparan Sulfate Organizes Neuronal Synapses through Neurexin Partnerships.  Cell 174(6): 1450--1464.e23.

FBrf0242409

Research paper

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.

PMC6173057 (PMC) (EuropePMC)