Linker molecules between laminins and dystroglycan ameliorate laminin-α2–deficient muscular dystrophy at all disease stages

Abstract

Mutations in laminin-α2 cause a severe congenital muscular dystrophy, called MDC1A. The two main receptors that interact with laminin-α2 are dystroglycan and α7β1 integrin. We have previously shown in mouse models for MDC1A that muscle-specific overexpression of a miniaturized form of agrin (mini-agrin), which binds to dystroglycan but not to α7β1 integrin, substantially ameliorates the disease (Moll, J., P. Barzaghi, S. Lin, G. Bezakova, H. Lochmuller, E. Engvall, U. Muller, and M.A. Ruegg. 2001. Nature. 413:302–307; Bentzinger, C.F., P. Barzaghi, S. Lin, and M.A. Ruegg. 2005. Matrix Biol. 24:326–332.). Now we show that late-onset expression of mini-agrin still prolongs life span and improves overall health, although not to the same extent as early expression. Furthermore, a chimeric protein containing the dystroglycan-binding domain of perlecan has the same activities as mini-agrin in ameliorating the disease. Finally, expression of full-length agrin also slows down the disease. These experiments are conceptual proof that linking the basement membrane to dystroglycan by specifically designed molecules or by endogenous ligands, could be a means to counteract MDC1A at a progressed stage of the disease, and thus opens new possibilities for the development of treatment options for this muscular dystrophy.

Congenital muscular dystrophy. Part II: a review of pathogenesis and therapeutic perspectives

“…Mini-agrin not only ameliorates the phenotype in those mice but also decelerates disease progression when applied at late stages. Meinen et al 109 demonstrated that full-length agrin is also capable of promoting this improvement This result indicates the role of DG not only in the pathogenesis of CMDs caused by hypoglycosilation of alpha-DG, but also in MDC1A. The improvement of the phenotype may be due to the link between 'non-muscle' laminins and DG through miniagrin, therefore maintaining the sarcollema stability.…”

“…The improvement of the phenotype may be due to the link between 'non-muscle' laminins and DG through miniagrin, therefore maintaining the sarcollema stability. These authors 109 also supposed that since the genetic manipulation in dy W /dy W mice can prevent apoptosis, it might be possible that antitiapoptotic agents act synergistically with mini-agrin. Therefore, a future therapeutic attempt for patients with MDC1A could be the combination of antiapoptotic drugs with the expression of mini-agrin in muscle, and/or the up-regulation of endogenous agrin.…”

“…From 1994, knock-out mouse or spontaneous mutant mouse strains have been identified as animal models for MDC1A with total and partial deficiency [99][100][101][102][103][104][105] , and experimental therapeutic strategies have been attempted 102,103,[106][107][108][109][110][111][112][113][114][115][116] . In mice, Kuang et al 102,103 were successful in obtaining the expression of a human laminin alpha 2 chain transgene under the regulation of a muscle-specific creatine kinase promoter.…”

Basement membranes and human disease

“…Importantly improving the interaction between laminin and dystroglycan through the administration of linker molecules or agrin ameliorates the dystrophy in mice (Meinen et al 2007;Moll et al 2001), which was also observed through inhibition of apoptosis by increased BCL2 expression (Dominov et al 2005;Girgenrath et al 2004), thereby providing potential therapeutic avenues.…”

A mutation-independent approach via transcriptional upregulation of a disease modifier gene rescues muscular dystrophy in vivo

“…In addition to Lama1 upregulation described in this study, a number of disease modifying strategies are currently being explored in MDC1A animal models, such as treatment with miniaturized agrin [20][21][22] and laminin-α1 LN-domain nidogen-1 (αLNNd) [23][24][25] . 27 .…”