GLYCOSYLATION Sweet Memories of Synapsins?

Long-term potentiation and task-specific learning both stimulate fucosylation of synaptic proteins; moreover, fucose-(1-2)-galactose [Fuc(1-2)gal], which covalently modifies N- and O-linked glycoproteins, has been implicated in learning and memory. However, the identity of the glycoproteins involved, and the mechanisms whereby fucosylation modifies their function, have been unclear. Murrey et al. used Western analysis to show that glycoproteins bearing Fuc(1-2)gal were present in rat hippocampal brain extracts and cultured hippocampal neurons. Immunostaining of cultured neurons that had formed synapses indicated that Fuc(1-2)gal was present on glycoproteins in presynaptic nerve terminals. The authors used a combination of techniques including subcellular fractionation, gel electrophoresis, MALDI-TOF MS, immunoprecipitation, and Western analysis to show that synapsins Ia and Ib were the predominant Fuc(1-2)gal glycoproteins in the adult rat hippocampus. When fucosylation of synapsin I expressed in HeLa cells was inhibited with 2-deoxy-D-galactose (2-dGal), the abundance of synapsin I decreased due to a reduction in its half-life; pharmacological analysis indicated that defucosylated synapsin was degraded by calpain (a calcium-dependent protease). 2-dGal also reduced synapsin I abundance in cultured hippocampal neurons and elicited neurite retraction, attenuated neurite outgrowth, and delayed synapse formation. Compared with wild-type neurons, neurons cultured from mice lacking synapsin I showed reduced neurite outgrowth and delayed formation of synapses, and the effects of 2-dGal on neurite length were markedly attenuated. Thus, the authors conclude that fucosylation can regulate synapsin I abundance and may help modulate neurite outgrowth and neuronal morphology.

H. E. Murrey, C. I. Gama, S. A. Kalovidouris, W.-I. Luo, E. M. Driggers, B. Porton, L. C. Hsieh-Wilson, Protein fucosylation regulates synapsin Ia/Ib expression and neuronal morphology in primary hippocampal neurons. Proc. Natl. Acad. Sci. U.S.A. 103, 21-26 (2006). [Abstract] [Full Text]