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Artificial restoration of the linkage between laminin and dystroglycan ameliorates the disease progression of MDC1A muscular dystrophy at all stages

Meinen, Sarina. Artificial restoration of the linkage between laminin and dystroglycan ameliorates the disease progression of MDC1A muscular dystrophy at all stages. 2005, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_7997

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Abstract

Laminin-α2 deficient congenital muscular dystrophy, classified as MDC1A, is a severe
progressive muscle-wasting disease that leads to death in early childhood. MDC1A is caused by
mutations in lama2, the gene encoding the laminin-α2 chain being part of laminin-2, the main
laminin isoform present in the extracellular matrix of muscles and peripheral nerves. Via selfpolymerization,
laminin-2 forms the primary laminin scaffold and binds with high affinity to α-
dystroglycan on the cell surface, providing a connection to the cytoskeleton via the
transmembranous protein β-dystroglycan. Deficiency in laminin-α2 leads to absence of laminin-2
and to upregulation of laminin-8, a laminin isoform that cannot self-polymerize and does not bind
to α-dystroglycan. Therefore, in laminin α2-deficient muscle the chain of proteins linking the
intracellular contractile apparatus via the plasma membrane to the extracellular matrix is
interrupted. Consequently, muscle fibers loose their stability and degenerate what finally leads to
a progressive muscle wasting.
In previous studies, we have shown that a miniaturized form of the extracellular matrix protein
agrin, which is not related to the disease-causing lama2 gene and was designed to contain highaffinity
binding sites for the laminins and for α-dystroglycan, was sufficient to markedly improve
muscle function and overall health in the dyW-/- mouse model of MDC1A. In a follow-up study we
provided additional evidence that mini-agrin, both increases the tolerance to mechanical load but
also improves the regeneration capacity of the dystrophic muscle.
We now report on our progress towards further testing the use of this approach for the treatment
of MDC1A. To test whether mini-agrin application after onset of the disease would still ameliorate
the dystrophic symptoms, we have established the inducible tetracycline-regulated “tet-off”
expression system in dyW-/- mice to temporally control mini-agrin expression in skeletal muscles.
We show that mini-agrin slows down the progression of the dystrophy when applied at birth or in
advanced stages of the disease. However, the extent of the amelioration depends on the
dystrophic condition of the muscle at the time of mini-agrin application. Thus, the earlier miniagrin
is applied, the higher is the profit of its beneficial properties.
In addition to gene therapeutical approaches, the increase of endogenous agrin expression levels
in skeletal muscles by pharmacologically active compounds would be a safe and promising
strategy for the treatment of MDC1A. To evaluate the potential and pave the way to further
expand on the development of such a treatment, we determined whether full-length agrin
ameliorates the dystrophic phenotype to a comparable extent as it was observed by application of
mini-agrin. We provide evidence that constitutive overexpression of chick full-length agrin in dyW-/-
muscle ameliorates the dystrophic phenotype, although not as pronounced as mini-agrin does.
In conclusion, our results are conceptual proof that linkage of laminin to the muscle fiber
membrane is a means to treat MDC1A at any stage of the disease. Our findings definitely
encourage to further expanding on this therapeutic concept, especially in combination with
treatment using functionally different approaches. Moreover, these experiments set the basis for
further developing clinically feasible and relevant application methods such as gene therapy4
and/or the screening of small molecules able to upregulate production of agrin in muscle.
Advisors:Rüegg, Markus A.
Committee Members:Meier, Thomas
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Neurobiology > Pharmacology/Neurobiology (Rüegg)
UniBasel Contributors:Rüegg, Markus A.
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:7997
Thesis status:Complete
Bibsysno:Link to catalogue
Number of Pages:89
Language:English
Identification Number:
Last Modified:22 Apr 2018 04:30
Deposited On:13 Feb 2009 16:14

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