Eur opean Rev iew for Med ical and Pharmacol ogical Sci ences 2016; 20: 3683-3687 induced muscular dystrophies – a review

Q.-Z. ZHANG

Department of Neurology, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China Department of Neurology, The Fifth People’s Hospital of Jinan, Jinan, Shandong, China

Abstract. – Dystroglycanopathies are mus - dystrophies caused predominantly by mutations cular dystrophies caused by mutations in in genes involved in the O-linked glycosylation involved the in O-linked glycosylation of -dys - 2 α of α-dystroglycan . troglycan. Severe forms of these conditions re - In addition to muscle dystrophy, a constella - sult in abnormalities in exhibit brain and ocular developmental too, in addition to muscular dys - tion of brain anomalies, ranging from mild cog - trophy. The full spectrum of developmental nitive impairment to severe mental retardation, pathology is caused mainly by loss of dystrogly - with or without structural malformations, is pre - can from Bergmann glia. Moreover, cognitive sented in these maladies; yet what role dystrogly - deficits are constant features of severe forms of can plays in the remains dystroglycanopathies. However, the precise mol - largely undiscovered. Thus, understanding how ecular mechanism leading to neuronal dysfunc - tion in these diseases is not fully known yet. The the dystroglycan contributes to brain de - present review article will discuss the impor - velopment in general, and cerebellar histogenesis tance of dystroglycan in cerebellar development in particular, is imperative to elucidate the mech - and associated pathological states. anisms leadings to dystroglycanopathy-associat - ed cerebellar dysplasia. The present review shall Key Words: be focused on the above theme and will explore Dystroglycan, Cerebellar development, Dystrogly - all important associated areas. canpathies . Dystroglycanopathy and Congenital The common biochemical hallmark for these Introduction diseases is hypoglycosylation and reduced lig - 3 and-binding affinity of α-DG . These dystrophies Cobblestone lissencephaly belongs to a cate - present a broad clinical spectrum, ranging from gory of disorders characterized by structural mal - congenital muscular dystrophy (CMD) with brain formation of the brain, caused by defects in neu - and eye involvement in severe cases to limb-gir - ronal migration during early development 1. The dle muscular dystrophy (LGMD) in milder in - cobblestone phenotype is the result of neuroglial stances 4. CMD is a heterogeneous group of dis - over migration into the subarachnoid space, lead - eases with autosomal recessive inheritance, char - ing to the formation of an additional cortical lay - acterized by the onset of hypotonia, muscle er; the ramification is heterotopia that produces weakness, contractures at birth or within the first an unusually “bumpy ” brain surface. Clinical few months of life, and by dystrophic changes representations of this disorder include cortical visible in the muscle biopsy. The clinical diversi - dysplasia, dysmyelination, and pontocerebellar ty of CMD is shown by the different degrees of dysplasia. The presence of cobblestone delay in motor developmental, physical disabili - lissencephaly is pathognomonic of a group of ty, muscle pathology, and by presence or absence congenital muscular dystrophies: Walker-War - of mental retardation. burg syndrome, muscle-eye-brain disease, and Within the brain, dystroglycan is expressed in Fukuyama congenital muscular dystrophy. These astrocytic endfeet abutting the glia limitans and diseases are the severe manifestations of a het - the intracerebral vasculature 5. In addition to be - erogeneous group of autosomal recessive disor - ing localized at the inner limiting membrane ders termed “dystroglycanopathies ” – muscular and the basal laminae of blood vessels, DG is

Corresponding Author: Qizhi Zhang, MD; e-mail: [email protected] 3683 Q.-Z. Zhang expressed by photoreceptor cells in the outer the protein component of the basal lamina plexiform layer of the 6. In addition to which surrounds muscle fibers, cause merosin- this , DG has been confirmed to be expressed deficient muscular dystrophy 14,15 . This corrobo - important brain parts including all major neu - rates the perception that any disruption to the rons and glia in the developing central nervous DGC-linked ECM and muscle fiber cytoskele - system 7. On the other hand, a study in recent ton, whether it be minimized expression of the past has confirmed its presence in the develop - protein component of the , ing cerebellum, in granule cell precursors, Purk - or diminished ligand binding capability of DG, inje cells, radial glia, and Bergmann glia 8. Fur - or reduced expression of the DGC, is sufficient thermore , in the BM receptors, dystroglycan is to cause muscular dystrophy. present as -glycoprotein Complex comprised of an extracellular -subunit and a Post-translational modification of 9 α transmembrane β-subunit . The physiological α-Dystroglycan studies about its functional evaluation con - Dystroglycan (DG) is a glycoprotein that un - firmed the involvement of DG in diverse cellu - dergoes glycosyltransferase -mediated N-glyco - lar functions like membrane in - sylation, mucin-type O-glycosylation, O-man - tegrity maintenance, structural as well as func - nosylation, and an identified phosphorylated O- tional regulation of the CNS and skeletal mus - mannosyl glycan bearing xylose and glucuronic cle regulation 10,11 . Besides this, the precise func - acid-containing polysaccharide. Loss of N- tion of the DGC remains to be described, but it linked glycosylation on DG has no affect on its is suggested to bestow sarcolemmal stability ability to bind its ligand; however, loss of O- during . So, far it is now cer - linked glycosylation appears to disrupt DG-lig - tain that genetic causes of various reported mus - and binding 16 . As it happens, defects in O-man - cular dystrophies are associated with mutations nosyl glycan synthesis, caused by mutations in in various components of DGC . genes required for α-DG glycosylation, give In addition to DG and dystrophin, the core rise to congenital disorders termed dystrogly - of the DGC in skeletal muscle are the canopathies. Biochemical analysis on skeletal - sub-complex, whose muscle biopsy from these patients revealed the purported function is to stabilize the whole hallmarks of dystroglycanopathy: hypoglycosy - DGC within the . Indeed, mutations lated α-DG, reduced expression of α2, in either sarcoglycans or dystrophin reduce the and reduced laminin-binding capability, sug - expression or perturb the formation of the entire gesting a connection between CDG and dystro - DGC, and are thought to be one of the underly - glycanopathy. ing mechanisms responsible for their respective muscular dystrophies. Additional components Extracellular Interactions of Dystroglycan of the DGC include dystrobrevins and syn - Dystroglycan (DG) is ubiquitously expressed trophins, two types of dystrophin-binding pro - in a number of tissues and has, thus, been associ - teins that do not appear to have direct roles in ated with several proteins of multiple functions. the mechanical function of the DGC, but rather Notwithstanding the omnipresent distribution serve as docking sites for other intracellular sig - and the numerous binding partners, DG has been naling proteins 12 . Mutation in the dystroglycan studied most extensively in muscle, particularly (DAG1) itself or mutations in genes en - in relation to its role in the dystrophin-glycopro - coding known and putative glycosyltransferases tein complex and associated muscular dystro - – enzymes involved in the post-translational phies, while much less is known about its func - 17 modifications of α-DG – lead to a group of het - tions in the brain . This section will describe the erogeneous muscular dystrophies; these dystro - significance of DG-ligand interplays in the con - phies have a spectrum of clinical manifestations text of brain development and disease, focusing ranging from limb-girdle phenotypes to severe on extracellular interactions via the numerous brain and eye malformations and mental retar - glycans on -DG. The mucin domain of -DG is 13 α α dation . Hypoglycosylation of α-DG and ensu - in fact decorated with O-linked glycans, amongst ing reduced ligand binding affinity is the under - which the phosphorylated O-mannose polysac - lying mechanism leading to disease manifesta - charide was recently identified to be crucial for 18 tion. Meanwhile, mutations in the LAMA2 gene α-DG ’s ligand-binding affinity . α-DG binds to encoding the α2 subunit of laminin (merosin), laminin G (LG) domain-containing proteins in

3684 Dystroglycan induced muscular dystrophies – a review the extracellular space, including components of tor ribbon 27 . In the visual system, pho - the basement membrane (BM) such as , toreceptors detect and distinguish a wide range laminin, and , synaptic adhesion mole - of light intensities, then transmit the received cules α- and β-neurexins, at light information to bipolar and horizontal cells the photoreceptor , and slit at the in the retina using a special type of synapse spinal cord ventral midline 19-21 . Collectively, called ribbon synapse. The ribbon synapse en - studies of α-DG interactions with LG-domain- ables the graded and rapid release of synaptic containing proteins in the brain support the no - vesicles and faithfully transmits a broad range of tion that DG is crucial for the proper laminar or - light intensity information. ganization and structural development of the DG is expressed at the presynaptic terminals CNS. of photoreceptors and forms complexes with Laminin, perlecan, and agrin are protein com - pikachurin at the synaptic cleft via interaction be - 28 ponents of the BM, matrix extension of the plas - tween α-DG and LG domains of pikachurin . ma membrane which serves to protect tissue Oligomerization of pikachurin induces DG clus - from physical stress as well as provide structural tering on the photoreceptor surface; conversely, support for cell differentiation, polarization, mi - DG expression is required for the accumulation gration, and survival 22 . Laminin is a heterotrimer of pikachurin. Such bidirectional interaction is consisting of one each of five α, four β, and three required for proper ribbon synapse ’s structural γ subunits joined at the coiled-coil domain. The formation and subsequent retinal electrophysiol - N-terminals of the three laminin chains ( α, β, ogy. Slits are secreted proteins at the floor plate and γ) form ternary nodes that are essential for that act as chemorepellents for commissural ax - laminin polymerization, whereas only the C-ter - onal projections from spinal cord neurons 29 . minal of laminin α chain participates in cell sur - Roundabouts (Robo) are canonical transmem - face adhesion via interactions between the last brane receptors for Slits; Slit-Robo binding is 23 30 two of its LG domains (LG4, LG5) and α-DG . further stabilized by the HSPG syndecan . Com - Perlecan and agrin are both LG domain-contain - missural axons are initially attracted to the mid - ing heparan sulfate proteoglycans (HSPG) that line by the chemoattractant Netrin acting through bind to both laminin and α-DG, forming a collat - its receptor, deleted in colorectal carcinoma eral linkage between laminin network and the (DCC), and are insensitive to Slits 31 . During mid - cell surface. These HSPGs are capable of binding line crossing commissural axons respond to Slits ’ to collagen, the only other polymerizing compo - repulsion due to upregulation of their surface ex - nent of the BM other than laminin, bridging and pression of Robo and, thus, are forced to exit compacting the two superstructures. Interactions from the midline to the contralateral side; at the between α-DG and these components of the BM same time , they are prevented from crossing back are thus critical for proper BM assembly and to the ipsilateral side. After crossing over, these maturation . axonal projections correspond to additional cues, including Slits, to turn and proceed to their Role of Neurexins synaptic targets. Neurexins are presynaptic adhesion molecules that form trans-synaptic complexes with postsy - naptic neuroligins through which synaptic trans - missions between neurons are mediated 24 . Conclusions -neuroligin interaction is required for proper synaptic function and cognition, as muta - The above researches make it clear that a lot of tions in neurexins and neuroligins are implicated work has been recorded in the literature revealing in autism spectrum disorders 25 . There are two importance of dystroglycan in cerebellar devel - types of neurexins: larger α-neurexins containing opment and disease. However, further studies are six LG domains intercalated by EGF-like do - still required to design efficient drugs for better mains, and shorter -neurexins containing a sin - management of the affected patients. 26 β gle LG domain . Both α-and β-neurexins bind to the mucin domain of α-DG, but the exact physio - logical functions of these interactions are not –––––––––––––––– –-– –– known . Pikachurin is an ECM-like retinal protein Conflict of Interest localized to the synaptic cleft in the photorecep - The Authors declare that there are no conflicts of interest.

3685 Q.-Z. Zhang

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3686 Dystroglycan induced muscular dystrophies – a review

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