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Pathogenic Participation of MuSK-Biglycan Linkage Contributive to Synaptic Stability and Signalings in Myasthenia Gravis

Biglycan, a member of small leucine-rich repeat proteoglycan family, expresses on the skeletal muscle surface and provides a critical link between the basal lamina and the cytoskeleton. As one of the extracellular matrix protains, the glycosaminoglycan-binding form of biglycan is concerned with a linkage to the actin cytoskeleton and thereby contributes to synaptic stability. In addition, as confirmed by the mutation experiment, the non-glycanated form of biglycan links to the muscle-specific tyrosine kinase (MuSK) extracellular domains (immunoglobulin-like domain 1 (Ig1 domain, mediating agrin-signaling) and cysteine-rich domain (CRD, mediating Wnt-signaling)) which constitute the postsynaptic receptive complex in cooperation with low-density lipoprotein receptor-related protein 4 (Lrp4), so that this form takes part in the rapsyn-anchored acetylcholine receptor clustering and possibly in the trans-synaptic communication mediated by Lrp4 and MuSK CRD. In the manner similar to the collagen Q-acetylcholinestease (AChE) complex, the linkage of biglycan with AChE contributes to the localized sensitivity to acetylcholine at the postsynaptic membrane. Since biglycan is an important constituent of the extracellular matrix positioned as the the MuSK-binding protein responsible for synaptic function, it is worth investigating to determine whether biglycan could be directly targeted by a humoral immune response. The antibody assay of biglycan was done in the serum samples from myasthenia gravis (MG) patients positive for antibodies against MuSK Ig1/2 domains and CRD, but we obtained negative results. However, taking the linkage of biglycan with MuSK into consideration, the MuSK antibodies in MG may cause an impairment in the synaptic stability based on the MuSK-linked biglycan, in addition to a misalignment in the pre- and post-synaptic functional organizations. We also briefly discuss about biglycan as a molecule regulating the multifunctional proinflammatory signaling and also participating in the MG thymus pathology (hyperplastic change) on one hand, and a molecule to counter the pathologies in skeletal muscle and bone formation on the other hand. The present review points out both signaling and structural roles of biglycan which has relations with MuSK function.


Masaharu Takamori*

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