title: Linker molecules between laminins and dystroglycan ameliorate laminin-alpha2-deficient muscular dystrophy at all disease stages.
abstract: Mutations in laminin-alpha2 cause a severe congenital muscular dystrophy, called MDC1A. The two main receptors that interact with laminin-alpha2 are dystroglycan and alpha7beta1 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 alpha7beta1 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.
authors: Biozentrum, University of Basel, CH-4056 Basel, Switzerland.
authors: Sarina
authors: S
authors: Meinen
authors: Patrizia
authors: P
authors: Barzaghi
authors: Shuo
authors: S
authors: Lin
authors: Hanns
authors: H
authors: Lochmüller
authors: Markus A
authors: MA
authors: Ruegg
mesh_terms: D018171:Agrin / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001485:Basement Membrane / Q000187:drug effects / Q000378:metabolism; D001665:Binding Sites / Q000502:physiology; D002478:Cells, Cultured; D002642:Chick Embryo; D004195:Disease Models, Animal; D018450:Disease Progression; D049030:Dystroglycans / Q000378:metabolism*; D015316:Genetic Therapy / Q000379:methods; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D007797:Laminin / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism* / Q000503:physiopathology; D009137:Muscular Dystrophy, Animal / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy*; D017434:Protein Structure, Tertiary / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D016896:Treatment Outcome
chemical_list: D018171:Agrin; D019812:Heparan Sulfate Proteoglycans; D007797:Laminin; D011993:Recombinant Fusion Proteins; C102645:laminin alpha 2; C071927:perlecan; D049030:Dystroglycans