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

doi:10.1073/pnas.0503381102

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

^*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 review April 24, 2005)

Abstract

Although fucose-α(1-2)-galactose [Fucα(1-2)Gal] carbohydrates have been implicated in cognitive processes such as long-term memory, the molecular mechanisms by which these sugars influence neuronal communication are not well understood. Here, we present molecular insights into the functions of Fucα(1-2)Gal sugars, demonstrating that they play a role in the regulation of synaptic proteins and neuronal morphology. We show that synapsins Ia and Ib, synapse-specific proteins involved in neurotransmitter release and synaptogenesis, are the major Fucα(1-2)Gal glycoproteins in mature cultured neurons and the adult rat hippocampus. Fucosylation has profound effects on the expression and turnover of synapsin in cells and protects synapsin from degradation by the calcium-activated protease calpain. Our studies suggest that defucosylation of synapsin has critical consequences for neuronal growth and morphology, leading to stunted neurite outgrowth and delayed synapse formation. We also demonstrate that Fucα(1-2)Gal carbohydrates are not limited to synapsin but are found on additional glycoproteins involved in modulating neuronal architecture. Together, our studies identify important roles for Fucα(1-2)Gal sugars in the regulation of neuronal proteins and morphological changes that may underlie synaptic plasticity.

Footnotes

↵ § To whom correspondence should be addressed. E-mail: lhw{at}caltech.edu.
Author contributions: H.E.M., C.I.G., and L.C.H.-W. designed research; H.E.M., C.I.G., S.A.K., W.-I.L., and E.M.D. performed research; 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: Fucα(1-2)Gal, fucose-α(1-2)-galactose; LTP, long-term potentiation; 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.