Our trails and trials in the subsarcolemmal cytoskeleton network and muscular dystrophy researches in the dystrophin era.
In 1987, about 150 years after the discovery of Duchenne muscular dystrophy (DMD), its responsible gene, the dystrophin gene, was cloned by Kunkel. This was a new substance. During these 20 odd years after the cloning, our understanding on dystrophin as a component of the subsarcolemmal cytoskeleton networks and on the pathomechanisms of and experimental therapeutics for DMD has been greatly enhanced. During this paradigm change, I was fortunately able to work as an active researcher on its frontiers for 12 years. After we discovered that dystrophin is located on the cell membrane in 1988, we studied the architecture of dystrophin and dystrophin-associated proteins (DAPs) complex in order to investigate the function of dystrophin and pathomechanism of DMD. During the conduct of these studies, we came to consider that the dystrophin-DAP complex serves to transmembranously connect the subsarcolemmal cytoskeleton networks and basal lamina to protect the lipid bilayer. It then became our working hypothesis that injury of the lipid bilayer upon muscle contraction is the cause of DMD. During this process, we predicted that subunits of the sarcoglycan (SG) complex are responsible for respective types of DMD-like muscular dystrophy with autosomal recessive inheritance. Our prediction was confirmed to be true by many researchers including ourselves. In this review, I will try to explain what we observed and how we considered concerning the architecture and function of the dystrophin-DAP complex, and the pathomechanisms of DMD and related muscular dystrophies.
National Center of Neuroscience, NCNP, Kodairashi, Tokyo 187-8502, Japan. ozawa@ncnp.go.jp
Eijiro
E
Ozawa
D000199:Actins / Q000737:chemistry; D000818:Animals; D001671:Biochemistry / Q000266:history; D003001:Cloning, Molecular; D003599:Cytoskeleton / Q000378:metabolism*; D016189:Dystrophin / Q000378:metabolism / Q000502:physiology*; D049673:History, 20th Century; D006801:Humans; D007797:Laminin / Q000378:metabolism; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D020388:Muscular Dystrophy, Duchenne / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D058088:Sarcoglycanopathies / Q000378:metabolism; D012508:Sarcolemma / Q000378:metabolism*
D000199:Actins; D016189:Dystrophin; D007797:Laminin; D008051:Lipid Bilayers