Distinct roles of the dystrophin–glycoprotein complex: α-dystrobrevin and α-syntrophin in the maintenance of the postsynaptic apparatus of the neuromuscular synapse

Abstract

α-syntrophin (α-syn) and α-dystrobrevin (α-dbn), two components of the dystrophin-glycoprotein complex, are essential for the maturation and maintenance of the neuromuscular junction (NMJ) and mice deficient in either α-syn or α-dbn exhibit similar synaptic defects. However, the functional link between these two proteins and whether they exert distinct or redundant functions in the postsynaptic organization of the NMJ remain largely unknown. We generated and analyzed the synaptic phenotype of double heterozygote (α-dbn+/−, α-syn+/−), and double homozygote knockout (α-dbn−/−; α-syn−/−) mice and examined the ability of individual molecules to restore their defects in the synaptic phenotype. We showed that in double heterozygote mice, NMJs have normal synaptic phenotypes and no signs of muscular dystrophy. However, in double knockout mice (α-dbn−/−; α-syn−/−), the synaptic phenotype (the density, the turnover, and the distribution of AChRs within synaptic branches) is more severely impaired than in single α-dbn−/− or α-syn−/− mutants. Furthermore, double mutant and single α-dbn−/− mutant mice showed more severe exercise-induced fatigue and more significant reductions in grip strength than single α-syn−/− mutant and wild-type. Finally, we showed that the overexpression of the transgene α-syn-GFP in muscles of double mutant restores primarily the abnormal extensions of membrane containing AChRs that extend beyond synaptic gutters and lack synaptic folds, whereas the overexpression of α-dbn essentially restores the abnormal dispersion of patchy AChR aggregates in the crests of synaptic folds. Altogether, these data suggest that α-syn and α-dbn act in parallel pathways and exert distinct functions on the postsynaptic structural organization of NMJs.

Nerve-independent formation of membrane infoldings at topologically complex postsynaptic apparatus by caveolin-3

“…On the other hand, mutations in the caveolin-3 gene causing the loss of caveolin-3 expression are responsible for an autosomal dominant form of limb-girdle muscular dystrophy (LGMD) ( 57 ). These studies indicate that the precise control of endogenous caveolin-3 expression levels is essential for maintaining normal NMJ structures and function, as well as for organizing the dystrophin-glycoprotein complex that is important for the maturation and maintenance of the postsynaptic apparatus ( 58 ). As membrane infoldings are developed in association with ECM-induced aneural and synaptic AChR clusters in Xenopus primary muscle cultures that has been used as a cell-based assay for studying the pathogenesis of myasthenia gravis ( 59 ), this assay could be applied for investigating the formation and maintenance of membrane infoldings at AChR clusters in human primary muscle cultures derived from DMD or LGMD patients.…”