Chemistry Reference
In-Depth Information
which provide the physiological basis of neuronal excitability. The nicotinic
cholinergic receptor channel, for example, consists of fi ve subunits that are glyco-
sylated with a total of about 75 carbohydrate residues. Virtually all the monosac-
charides found in GSLs are expressed in the glycans attached to proteins. As with
GSLs, this diversity is cell-type specifi c and developmentally regulated. Glycopro-
teins of the nervous system, as for other tissues, contain either
N
- glycan or
O
-
glycan oligosaccharides depending on the nature of their linkage to the protein
backbone. Biosynthetic pathways, involving coordinate processing by the rough
endoplasmic reticulum and Golgi apparatus, differ signifi cantly for these two
groups (please see Chapters 6 and 7). The opportunities for inherited defects in
glycan biosynthesis leading to neurological disorders are thus manifold, and were
shown to result in epilepsy, psychomotor disturbance and mental retardation,
among others (please see Chapter 22). In general, the more upstream the blockade
of synthesis, the more severe the pathology. Glycan structures in all their complex-
ity are undoubtedly a necessary feature of the enormously complex array of neu-
ronal, glial, and other cell types and subtypes that interact in multiple ways in the
developing and mature nervous system. As indicated below, neural recognition
molecules are vital to developmental processes, while myelin glycoproteins have
received special attention in relation to their role in blocking regeneration.
A dynamic posttranslational modifi cation found in neural (and virtually all
metazoan) cells involves transfer of GlcNAc from UDP-GlcNAc to Ser/Thr resi-
dues without further elongation (please see Chapter 7.4.2 and Table 7.8). Promi-
nent in, but not limited to nuclei, this reaction is necessary for cell viability.
Evidence suggests that
O
- GlcNAc and
O
-phosphate are reciprocal and compete for
the same Ser/Thr residues. It was recently found that phosphorylation of tau
protein is inversely regulated by
O
-GlcNAcylation and that abnormal hyperphos-
phorylation of tau, which leads to neurofi brillary degeneration in Alzheimer's
disease, can be caused by the decreased glucose metabolism and
O
- GlcNAcylation
that characterize this disorder [20]. This is one of many theories pointing to gly-
coconjugate involvement in the etiology of Alzheimer' s disease.
30.7
Neural Recognition Glycoproteins
Neural recognition molecules in general have a major role in signaling mecha-
nisms and cell-cell interactions that regulate neural development. The polysialic
acid (PSA; please note:
Pisum sativum
agglutinin in Table 18.1 is also abbreviated
as PSA) glycan is a linear homopolymer of variable length amounting to 50 or
more sialic acid residues, all joined by 2,8 linkages (see gangliosides GD1b and
GT1b of Figure 30.2 for depiction of this linkage). These chains are linked to two
N
-glycans located in the fi fth immunoglobulin-like domain of the neural cell adhe-
sion molecule (NCAM), forming one of the most abundant glycan structures
in the developing mammalian nervous system. The three known isoforms of
NCAM vary in terms of molecular weight, mode of membrane attachment and
