Polysialylation of the Neural Cell Adhesion Molecule: Setting the Stage for Plasticity Across Scales of Biological Organization

Abstract

In vertebrates, the neuronal cell adhesion molecule ({NCAM}/{CD}56) has 3 isoforms resulting from alternative splicing that differ by their size (120, 140 and 180 {kDa}) and their anchoring at the membrane. Whereas {NCAM}120 is glycophosphatidyl inositol anchored, {NCAM}140 and {NCAM}180 are transmembrane molecules. {NCAM}180 has an additional intracellular 267 amino acids insert, that differentiate it from {NCAM}140, but its role remains to be fully elucidated. There are differences regarding the specificity and the level of expression of these isoforms in different cells of the nervous system. Whereas {NCAM}120 and {NCAM}140 are preferentially expressed in glial cells {NCAM}180 seems to be prevalent on neurons. Although differences in expression and function of the {NCAM} isoforms exist, one common denominator is that they can be post-translationally modified by the addition of long, linear chains of α2,8-linked Nacetylneuraminic acid (Neu5Ac) residues. In vertebrates, {NCAM} is the major acceptor of this unique carbohydrate. This modification occurs on the fifth immunoglobulin domain of {NCAM} located on the extracellular part of the membrane and common to all 3 isoforms. These polysialylated isoforms have emerged as particularly attractive candidates for promoting plasticity in the central nervous system ({CNS}). The large negatively charged polysialic acid ({PSA}) chain of {NCAM} is postulated to be a spacer that reduces adhesion forces between cells allowing dynamic changes in membrane contacts. However, recent studies indicate that a crucial function of {PSA} resides in controlling interactions mediated by {NCAM}. Accumulating evidence also suggests that {PSA}-{NCAM}-mediated interactions lead to activation of intracellular signals fundamental to biological functions. An important role of {PSA}-{NCAM} appears to be during development, when its expression level is high and where it contributes to the regulation of cell shape, growth or migration. However, {PSA}-{NCAM} does persist in adult brain structures such as the hippocampus that display a high degree of plasticity where