From the Cover: Protein fucosylation regulates synapsin Ia/Ib expression and neuronal morphology in primary hippocampal neurons

doi:10.1073/pnas.0503381102

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Protein fucosylation regulates synapsin Ia/Ib expression and neuronal morphology in primary hippocampal neurons

Heather E. Murrey^*, Cristal I. Gama^*, Stacey A. Kalovidouris^*, Wen.-I. Luo^*, Edward M. Driggers, Barbara Porton, and Linda C. Hsieh-Wilson^*,

^*Howard Hughes Medical Institute and Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 East California Boulevard, Pasadena, CA 91125; Ensemble Discovery Corporation, Cambridge, MA 02139; and Department of Psychiatry, New York University School of Medicine/Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962

Edited by Pietro De Camilli, Boyer Center for Molecular Medicine, New Haven, CT, and approved November 15, 2005

Received for publication April 24, 2005.

Abstract: Although fucose- ${alpha}$ (1-2)-galactose [Fuc ${alpha}$ (1-2)Gal] carbohydrateshave been implicated in cognitive processes such as long-termmemory, the molecular mechanisms by which these sugars influenceneuronal communication are not well understood. Here, we presentmolecular insights into the functions of Fuc ${alpha}$ (1-2)Gal sugars,demonstrating that they play a role in the regulation of synapticproteins and neuronal morphology. We show that synapsins Iaand Ib, synapse-specific proteins involved in neurotransmitterrelease and synaptogenesis, are the major Fuc ${alpha}$ (1-2)Gal glycoproteinsin mature cultured neurons and the adult rat hippocampus. Fucosylationhas profound effects on the expression and turnover of synapsinin cells and protects synapsin from degradation by the calcium-activatedprotease calpain. Our studies suggest that defucosylation ofsynapsin has critical consequences for neuronal growth and morphology,leading to stunted neurite outgrowth and delayed synapse formation.We also demonstrate that Fuc ${alpha}$ (1-2)Gal carbohydrates are not limitedto synapsin but are found on additional glycoproteins involvedin modulating neuronal architecture. Together, our studies identifyimportant roles for Fuc ${alpha}$ (1-2)Gal sugars in the regulation ofneuronal proteins and morphological changes that may underliesynaptic plasticity.

Key Words: fucose • glycosylation • neurite outgrowth • glycoprotein • calpain

Author contributions: H.E.M., C.I.G., and L.C.H.-W. designedresearch; H.E.M., C.I.G., S.A.K., W.-I.L., and E.M.D. performedresearch; B.P. contributed new reagents/analytic tools; H.E.M.,C.I.G., S.A.K., E.M.D., and L.C.H.-W. analyzed data; and H.E.M.,C.I.G., and L.C.H.-W. wrote the paper.

Conflict of interest statement: No conflicts declared.

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: Fuc ${alpha}$ (1-2)Gal, fucose- ${alpha}$ (1-2)-galactose; LTP, long-termpotentiation; DIV, days in vitro; En, embryonic day n; NSF,N-ethylmaleimide-sensitive factor; 2-dGal, 2-deoxy-D-galactose;6-dGal, 6-deoxy-D-galactose.

To whom correspondence should be addressed. E-mail: lhw{at}caltech.edu.

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