Glycan susceptibility factors in autism spectrum disorders

Abstract

Idiopathic autism spectrum disorders (ASDs) are neurodevelopmental disorders with unknown etiology. An estimated 1:68 children in the U.S. are diagnosed with ASDs, making these disorders a substantial public health issue. Recent advances in genome sequencing have identified numerous genetic variants across the ASD patient population. Many genetic variants identified occur in genes that encode glycosylated extracellular proteins (proteoglycans or glycoproteins) or enzymes involved in glycosylation (glycosyltransferases and sulfotransferases). It remains unknown whether "glycogene" variants cause changes in glycosylation and whether they contribute to the etiology and pathogenesis of ASDs. Insights into glycan susceptibility factors are provided by studies in the normal brain and congenital disorders of glycosylation, which are often accompanied by ASD-like behaviors. The purpose of this review is to present evidence that supports a contribution of extracellular glycans and glycoconjugates to the etiology and pathogenesis of idiopathic ASDs and other types of pervasive neurodevelopmental disorders.

Keywords: Autism; Autism spectrum disorders; Brain extracellular matrix; Dystroglycanopathies; Glycans; Glycosaminoglycans; Glycosylation; Glycosyltransferase; Polysialic acid; Proteoglycans.

Fig. 1

Common classes of animal glycans found in the extracellular environment of the brain. The glycans are depicted as parts of hypothetical glycoconjugates. The representative sugars are depicted by colored symbols as described in the legend. GalNAc, N-acetylgalactosamine; GlcNAc, N-acetylglucosamine; Gal, galactose; Glc, glucose; Man, mannose; Fuc, fucose; Xyl, xylose; GlcA, glucuronic acid; IdoA, iduronic acid. (Figure modified and reprinted with permission from Chapter 1 from Essentials of Glycobiology, 2nd edition).

Fig. 2

Extracellular substructures in the brain. The organization of free glycans and glycoconjugates in extracellular substructures in the brain is depicted. (A) Organization of the pial basement membrane is supported by interactions between glycosylated dystroglycan and extracellular matrix proteins. (B) The interstitial neural extracellular matrix fills the extracellular space between cells in the brain and is comprised predominately of secreted hyaluronan (HA), chondroitin sulfate proteoglycans (CSPGs), hyaluronan and link proteins (HAPLNs), and shed heparan sulfate proteoglycans (HSPGs). (C) The cell surface glycocalyx is comprised of glycoconjugates localized to the plasma membrane including glycosphingolipids, heparan sulfate proteoglycans (HSPGs), glycosylated dystroglycan, and glycoproteins carrying N- or O-linked glycans (e.g. polysialylated NCAM, PSA-NCAM). Constituents of the cell surface glycocalyx are also abundant in neuronal synapses (inset).