The roles of dystroglycan in the nervous system: insights from animal models of muscular dystrophy

Abstract

Dystroglycan is a cell membrane protein that binds to the extracellular matrix in a variety of mammalian tissues. The α-subunit of dystroglycan (αDG) is heavily glycosylated, including a special O-mannosyl glycoepitope, relying upon this unique glycosylation to bind its matrix ligands. A distinct group of muscular dystrophies results from specific hypoglycosylation of αDG, and they are frequently associated with central nervous system involvement, ranging from profound brain malformation to intellectual disability without evident morphological defects. There is an expanding literature addressing the function of αDG in the nervous system, with recent reports demonstrating important roles in brain development and in the maintenance of neuronal synapses. Much of these data are derived from an increasingly rich array of experimental animal models. This Review aims to synthesize the information from such diverse models, formulating an up-to-date understanding about the various functions of αDG in neurons and glia of the central and peripheral nervous systems. Where possible, we integrate these data with our knowledge of the human disorders to promote translation from basic mechanistic findings to clinical therapies that take the neural phenotypes into account.

Keywords: Animal models; Brain development; Dystroglycan; Muscular dystrophy.

Fig. 1.

Molecular pathogenesis of α-dystroglycanopathies. (A) Schematic of dystroglycan protein interactions based on biochemical and functional evidence. A truncated form of αDG is most likely on display at the membrane surface, as the N-terminal region is cleaved during Golgi processing (Kanagawa et al., 2004). Matriglycan chains on the central mucin domain of αDG bind directly to laminin in the overlying basement membrane, while βDG is linked to the intracellular actin cytoskeleton through dystrophin. (B) Mutations in glycosyltransferase genes responsible for matriglycan construction cause a hypoglycosylation of αDG, resulting in loss of αDG-laminin binding and disruption of cell-matrix interaction. nNOS, neuronal nitric oxide synthase.

Fig. 2.

Glycosylation of α-dystroglycan. A simplified representation of the post-translational modifications on αDG, with arrows indicating each enzyme's respective glycan additions. POMT1/POMT2 catalyze the first step of glycosylation by adding an O-linked mannose to αDG in a process called O-mannosylation. The LARGE glycosyltransferase catalyzes the final step for the installation of the matriglycan, a repeating disaccharide of variable length that directly binds extracellular laminin. Other enzymes have been shown to be indirectly involved in αDG glycosylation through the synthesis of cytidine diphosphate ribitol (CDP-Rbo) and dolichol phosphate mannose (Dol-P-Man). Pathogenic mutations in each enzyme listed here are linked to the wide clinical spectrum of the α-dystroglycanopathies. For a detailed review, see Kanagawa and Toda, 2017.

Fig. 3.

Neural phenotypes in α-dystroglycanopathies. (A) Diagram of the nervous system regions primarily affected in α-dystroglycanopathies. Gross malformations are commonly reported in the brain and eyes and can include displaced neurons and glia (heterotopia), and abnormally small pons and cerebellum (pontocerebellar hypoplasia). These structural phenotypes are often accompanied by functional deficits in cognition and vision (myopia) (Santavuori et al., 1989; Pihko et al., 1995; Cormand et al., 2001; von Renesse et al., 2014). (B) Healthy brain development involves radial migration of newborn neurons (white arrow) into laminae of the cortical plate. Radial glia anchored to the pial basement membrane act as a guiding scaffold. Cortical dysplasia in α-dystroglycanopathy models is characterized by discontinuity of the pial basement membrane, disorganization of radial glial endfeet, abnormal migration of cells into the subarachnoid space and disrupted cortical lamination. CP, cortical plate; GL, glia limitans; IZ, intermediate zone; MZ, marginal zone; PM, pia mater; SAS, subarachnoid space; SP, subplate; VZ, ventricular zone.