Abstract
BackgroundAside from muscle, brain is also a major expression site for dystrophin, the protein whose abnormal expression is responsible for Duchenne muscular dystrophy. Cognitive impairments are frequently associated with this genetic disease, we therefore studied the fate of brain and skeletal muscle dystrophins and dystroglycans in dystrophic animal models.ResultsAll dystrophin-associated glycoproteins investigated were reduced in dystrophic muscle fibres. In Dp427-deficient mdx brain and Dp71-deficient mdx-3cv brain, the expression of α-dystroglycan and laminin was reduced, utrophin isoforms were up-regulated and β-dystroglycan was not affected. Immunofluorescence localization of β-dystroglycan in comparison with glial, endothelial and neuronal cell markers revealed co-localization of von Willebrand factor with β-dystroglycan. Its expression at the endothelial-glial interface was preserved in dystrophin isoform-deficient brain from mdx and mdx-3cv mice. In addition, chemical crosslinking revealed that the Dp71 isoform exists in mdx brain predominantly as a monomer.ConclusionsThis suggests an association of β-dystroglycan with membranes at the vascular-glial interface in the forebrain. In contrast to dystrophic skeletal muscle fibres, dystrophin deficiency does not trigger a reduction of all dystroglycans in the brain, and utrophins may partially compensate for the lack of brain dystrophins. Abnormal oligomerization of the dystrophin isoform Dp71 might be involved in the pathophysiological mechanisms underlying abnormal brain functions.
Highlights
Aside from muscle, brain is a major expression site for dystrophin, the protein whose abnormal expression is responsible for Duchenne muscular dystrophy
While the Dp427(-M) isoform exists in skeletal muscle, the central nervous system conhttp://www.biomedcentral.com/1471-2121/2/2 tains additional shorter dystrophin molecules [13, 25]
Three dystrophin isoforms exist in brain: Dp427(-B), Dp140 and Dp71 (Fig. 1b)
Summary
Aside from muscle, brain is a major expression site for dystrophin, the protein whose abnormal expression is responsible for Duchenne muscular dystrophy. Integral or surface-associated proteins that are relatively tightly connected with dystrophin are represented by α-,β-, γ-, and δ-sarcoglycan [5], α- and β-dystroglycan [6], sarcospan [7], α-, β1-, and β2-syntrophin [8], α- and β-dystrobrevin [9], laminin-2 [10] and cortical actin [11]. The backbone of this sarcolemma-spanning protein assembly is formed by the http://www.biomedcentral.com/1471-2121/2/2 dystroglycans [6]. Since β-dystroglycan is tightly associated with the peripheral merosin-binding protein α-dystroglycan, this complex provides a stable linkage to the laminin α2chain in the basal lamina [10]
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