Limits...
Our trails and trials in the subsarcolemmal cytoskeleton network and muscular dystrophy researches in the dystrophin era.

Ozawa E - Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. (2010)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: National Center of Neuroscience, NCNP, Kodairashi, Tokyo 187-8502, Japan. ozawa@ncnp.go.jp

ABSTRACT
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.

Show MeSH

Related in: MedlinePlus

Reciprocal localization of dystrophin and utrophin on normal and DMD human sarcolemma. A & B, normal muscle; C & D, DMD muscle; A & C, anti-dystrophin antibody staining; and B & D, anti-utrophin antibody staining.
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3037518&req=5

fig02: Reciprocal localization of dystrophin and utrophin on normal and DMD human sarcolemma. A & B, normal muscle; C & D, DMD muscle; A & C, anti-dystrophin antibody staining; and B & D, anti-utrophin antibody staining.

Mentions: In the July 31 issue of Cell in 1987, I read Kunkel’s paper reporting the partial AA sequence of dystrophin.8) Immediately, I instructed Eguchi to start the polypeptide synthesis. Soon after, he produced and sent me two polypeptide fragments of dystrophin with 50 AA residues. Then, our team obtained two polyclonal antibodies against these polypeptides by conventional methods. Using these antibodies, Arahata stained the normal and DMD muscles. Our dystrophin antibodies clearly stained the sarcolemma in normal human but not in DMD in January 1988 (Fig. 2A & C). Thus, absence of dystrophin on the sarcolemma was the cause of DMD. In addition to this, Arahata observed that dystrophin was distributed evenly throughout the sarcolemmas of human skeletal muscles without discriminating red and white muscle fibers. The first paper on localization of dystrophin was published in the February 1988 issue of this journal (PJA).13) Luckily enough, our next paper similar to the PJA paper was published in Nature on June 30, 1988.14) No similar paper had yet been published from other laboratories, before our papers.


Our trails and trials in the subsarcolemmal cytoskeleton network and muscular dystrophy researches in the dystrophin era.

Ozawa E - Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. (2010)

Reciprocal localization of dystrophin and utrophin on normal and DMD human sarcolemma. A & B, normal muscle; C & D, DMD muscle; A & C, anti-dystrophin antibody staining; and B & D, anti-utrophin antibody staining.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3037518&req=5

fig02: Reciprocal localization of dystrophin and utrophin on normal and DMD human sarcolemma. A & B, normal muscle; C & D, DMD muscle; A & C, anti-dystrophin antibody staining; and B & D, anti-utrophin antibody staining.
Mentions: In the July 31 issue of Cell in 1987, I read Kunkel’s paper reporting the partial AA sequence of dystrophin.8) Immediately, I instructed Eguchi to start the polypeptide synthesis. Soon after, he produced and sent me two polypeptide fragments of dystrophin with 50 AA residues. Then, our team obtained two polyclonal antibodies against these polypeptides by conventional methods. Using these antibodies, Arahata stained the normal and DMD muscles. Our dystrophin antibodies clearly stained the sarcolemma in normal human but not in DMD in January 1988 (Fig. 2A & C). Thus, absence of dystrophin on the sarcolemma was the cause of DMD. In addition to this, Arahata observed that dystrophin was distributed evenly throughout the sarcolemmas of human skeletal muscles without discriminating red and white muscle fibers. The first paper on localization of dystrophin was published in the February 1988 issue of this journal (PJA).13) Luckily enough, our next paper similar to the PJA paper was published in Nature on June 30, 1988.14) No similar paper had yet been published from other laboratories, before our papers.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: National Center of Neuroscience, NCNP, Kodairashi, Tokyo 187-8502, Japan. ozawa@ncnp.go.jp

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus