H Fukuta-Ohi

Teikyo University Hospital, Edo, Tōkyō, Japan

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Publications (11)43.68 Total impact

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    ABSTRACT: Alpha-dystroglycan is a cell surface peripheral membrane protein which binds to the extracellular matrix, while beta-dystroglycan is a type I integral membrane protein which anchors alpha-dystroglycan to the cell membrane via the N-terminal extracellular domain. The complex composed of alpha- and beta-dystroglycan is called the dystroglycan complex. Although defects of the dystroglycan gene have not been identified as the primary causes of hereditary diseases in humans, secondary but significant abnormalities of the dystroglycan complex have been revealed in severe muscular dystrophies, including sarcoglycanopathy (LGMD2C, D, E and F). In this study, we investigated proteolytic processing of beta-dystroglycan and its effect on the extracellular matrix-cell membrane linkage in cardiomyopathic hamsters, the model animals of LGMD2F. Compared to normal controls, proteolytic processing of beta-dystroglycan was activated in the skeletal, cardiac and smooth muscles of cardiomyopathic hamsters and this resulted in the partial disruption of the dystroglycan complex in these tissues. These phenomena were observed from the early phase of muscle degeneration process. Our results suggest that proteolytic processing of beta-dystroglycan disrupts the extracellular matrix-cell membrane linkage via the dystroglycan complex and this may play a role in the molecular pathogenesis of muscle degeneration in cardiomyopathic hamsters.
    Neuromuscular Disorders 01/2004; 13(10):796-803. · 3.46 Impact Factor
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    ABSTRACT: α-Dystroglycan is a cell surface peripheral membrane protein which binds to the extracellular matrix, while β-dystroglycan is a type I integral membrane protein which anchors α-dystroglycan to the cell membrane via the N-terminal extracellular domain. The complex composed of α- and β-dystroglycan is called the dystroglycan complex. Although defects of the dystroglycan gene have not been identified as the primary causes of hereditary diseases in humans, secondary but significant abnormalities of the dystroglycan complex have been revealed in severe muscular dystrophies, including sarcoglycanopathy (LGMD2C, D, E and F). In this study, we investigated proteolytic processing of β-dystroglycan and its effect on the extracellular matrix–cell membrane linkage in cardiomyopathic hamsters, the model animals of LGMD2F. Compared to normal controls, proteolytic processing of β-dystroglycan was activated in the skeletal, cardiac and smooth muscles of cardiomyopathic hamsters and this resulted in the partial disruption of the dystroglycan complex in these tissues. These phenomena were observed from the early phase of muscle degeneration process. Our results suggest that proteolytic processing of β-dystroglycan disrupts the extracellular matrix–cell membrane linkage via the dystroglycan complex and this may play a role in the molecular pathogenesis of muscle degeneration in cardiomyopathic hamsters.
    Neuromuscular Disorders 01/2003; 13(10):796-803. · 3.46 Impact Factor
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    ABSTRACT: The dystroglycan complex is a membrane-spanning complex composed of two subunits, alpha- and beta-dystroglycan. alpha-dystroglycan is a cell surface peripheral membrane protein which binds to the extracellular matrix (ECM), whereas beta-dystroglycan is an integral membrane protein which anchors alpha-dystroglycan to the cell membrane. The dystroglycan complex provides a tight link between the ECM and cell membrane. Dysfunction of the dystroglycan complex has commonly been implicated in the molecular pathogenesis of severe forms of hereditary neuromuscular diseases, including Duchenne muscular dystrophy, Fukuyama-type congenital muscular dystrophy and sarcoglycanopathy (LGMD2C, -D, -E and -F). To begin to clarify the pathway by which the dysfunction of the dystroglycan complex could lead to muscle cell degeneration, we investigated the proteolytic processing of the dystroglycan complex in this study. We demonstrate that (i) a 30 kDa fragment of beta-dystroglycan is expressed in peripheral nerve, kidney, lung and smooth muscle, but not skeletal muscle, cardiac muscle or brain, and (ii) this fragment is the product of proteolytic processing of the extracellular domain of beta-dystroglycan by the membrane-associated matrix metalloproteinase (MMP) activity. Importantly, furthermore, we demonstrate that this processing disintegrates the dystroglycan complex. Our results indicate that the processing of beta-dystroglycan by MMP causes the disruption of the link between the ECM and cell membrane via the dystroglycan complex, which could have profound effects on cell viability. Based on these and previously reported findings, we propose a hypothesis that this processing may play a crucial role in the molecular pathogenesis of sarcoglycanopathy.
    Human Molecular Genetics 08/2001; 10(15):1563-9. · 7.69 Impact Factor
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    ABSTRACT: We have demonstrated previously 1) that the dystroglycan complex, but not the sarcoglycan complex, is expressed in peripheral nerve, and 2) that alpha-dystroglycan is an extracellular laminin-2-binding protein anchored to beta-dystroglycan in the Schwann cell membrane. In the present study, we investigated the transmembrane molecular architecture of the dystroglycan complex in Schwann cells. The cytoplasmic domain of beta-dystroglycan was co-localized with Dp116, the Schwann cell-specific isoform of dystrophin, in the abaxonal Schwann cell cytoplasm adjacent to the outer membrane. beta-dystroglycan bound to Dp116 mainly via the 15 C-terminal amino acids of its cytoplasmic domain, but these amino acids were not solely responsible for the interaction of these two proteins. Interestingly, the beta-dystroglycan-precipitating antibody precipitated only a small fraction of alpha-dystroglycan and did not precipitate laminin and Dp116 from the peripheral nerve extracts. Our results indicate 1) that Dp116 is a component of the submembranous cytoskeletal system that anchors the dystroglycan complex in Schwann cells, and 2) that the dystroglycan complex in Schwann cells is fragile compared with that in striated muscle cells. We propose that this fragility may be attributable to the absence of the sarcoglycan complex in Schwann cells.
    Journal of Biological Chemistry 04/1999; 274(12):8240-6. · 4.65 Impact Factor
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    ABSTRACT: Dystroglycan is encoded by a single gene and cleaved into two proteins alpha- and beta-dystroglycan by posttranslational processing. Recently, alpha-dystroglycan was demonstrated to be an extracellular laminin-binding protein anchored to the cell membrane by a transmembrane protein beta-dystroglycan in striated muscle and Schwann cells. However, the biological functions of the dystroglycan-laminin interaction remain obscure, and in particular, it is still unclear if dystroglycan plays a role in cell adhesion. In the present study, we characterized the role of dystroglycan in the adhesion of schwannoma cells to laminin-1. Immunochemical analysis demonstrated that the dystroglycan complex, comprised of alpha- and beta-dystroglycan, was a major laminin-binding protein complex in the surface membrane of rat schwannoma cell line RT4. It also demonstrated the presence of alpha-dystroglycan, but not beta-dystroglycan, in the culture medium, suggesting secretion of alpha-dystroglycan by RT4 cells. RT4 cells cultured on dishes coated with laminin-1 became spindle in shape and adhered to the bottom surface tightly. Monoclonal antibody IIH6 against alpha-dystroglycan was shown previously to inhibit the binding of laminin-1 to alpha-dystroglycan. In the presence of IIH6, but not several other control antibodies in the culture medium, RT4 cells remained round in shape and did not adhere to the bottom surface. The adhesion of RT4 cells to dishes coated with fibronectin was not affected by IIH6. The known inhibitors of the interaction of alpha-dystroglycan with laminin-1, including EDTA, sulfatide, fucoidan, dextran sulfate, heparin, and sialic acid, also perturbed the adhesion of RT4 cells to laminin-1, whereas the reagents which do not inhibit the interaction, including dextran, chondroitin sulfate, dermatan sulfate, and GlcNAc, did not. Altogether, these results support a role for dystroglycan as a major cell adhesion molecule in the surface membrane of RT4 cells.
    Journal of Biological Chemistry 06/1997; 272(21):13904-10. · 4.65 Impact Factor
  • 01/1997;
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    ABSTRACT: We have shown previously that alpha-dystroglycan with a molecular mass of 120 kDa is a Schwann cell receptor of laminin-2, the endoneurial isoform of laminin comprised of the alpha2, beta1, and gamma1 chains. In this paper, we show that Schwann cell alpha-dystroglycan is also a receptor of agrin, an acetylcholine receptor-aggregating molecule having partial homology to laminin alpha chains in the C terminus. Immunochemical analysis demonstrates that the peripheral nerve isoform of agrin is a 400-kDa component of the endoneurial basal lamina and is co-localized with alpha-dystroglycan surrounding the outermost layer of myelin sheath of peripheral nerve fibers. Blot overlay analysis demonstrates that both endogenous peripheral nerve agrin and laminin-2 bind to Schwann cell alpha-dystroglycan. Recombinant C-terminal fragment of the peripheral nerve isoform of agrin also binds to Schwann cell alpha-dystroglycan, confirming that the binding site for Schwann cell alpha-dystroglycan resides in the C terminus of agrin molecule. Furthermore, the binding of recombinant agrin C-terminal fragment to Schwann cell alpha-dystroglycan competes with that of laminin-2. All together, these results indicate that alpha-dystroglycan is a dual receptor for agrin and laminin-2 in the Schwann cell membrane.
    Journal of Biological Chemistry 10/1996; 271(38):23418-23. · 4.65 Impact Factor
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    ABSTRACT: Dystoroglycan is encoded by a single gene and cleaved into two proteins, alpha and beta-dystroglycan, by posttranslational processing. The 120kDa peripheral nerve isoform of alpha-dystroglycan binds laminin-2 comprised of the alpha 2, beta 1, and gamma 1 chains. In congenital muscular dystrophy and dy mice deficient in laminin alpha 2 chain, peripheral myelination is disturbed, suggesting a role for the dystroglycan- laminin interaction in peripheral myelinogenesis. To begin to test this hypothesis, we have characterized the dystroglycan-laminin interaction in peripheral nerve. We demonstrate that (1) alpha-dystroglycan is an extracellular peripheral membrane glycoprotein that links beta-dystroglycan in the Schwann cell outer membrane with laminin-2 in the endoneurial basal lamina, and (2) dystrophin homologues Dp116 and utrophin are cytoskeletal proteins of the Schwann cell cytoplasm. We also present data that suggest a role for glycosylation of alpha-dystroglycan in the interaction with laminin.
    Journal of Neurochemistry 05/1996; 66(4):1518-24. · 3.97 Impact Factor
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    ABSTRACT: Dystroglycan is encoded by a single gene and cleaved into two proteins, - and β-dystroglycan, by posttranslational processing. The 120-kDa peripheral nerve isoform of -dystroglycan binds laminin-2 comprised of the 2, β1, and 1 chains. In congenital muscular dystrophy and dy mice deficient in laminin 2 chain, peripheral myelination is disturbed, suggesting a role for the dystroglycan-laminin interaction in peripheral myelinogenesis. To begin to test this hypothesis, we have characterized the dystroglycan-laminin interaction in peripheral nerve. We demonstrate that (1) -dystroglycan is an extracellular peripheral membrane glycoprotein that links β-dystroglycan in the Schwann cell outer membrane with laminin-2 in the endoneurial basal lamina, and (2) dystrophin homologues Dp116 and utrophin are cytoskeletal proteins of the Schwann cell cytoplasm. We also present data that suggest a role for glycosylation of -dystroglycan in the interaction with laminin.
    Journal of Neurochemistry 03/1996; 66(4):1518 - 1524. · 3.97 Impact Factor
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    ABSTRACT: The absence of laminin alpha 2 chain causes muscle cell degeneration and peripheral dysmyelination in congenital muscular dystrophy patients and dy mice, suggesting its role in the maintenance of sarcolemmal architecture and peripheral myelinogenesis. Here we demonstrate the secretion of laminin alpha 2 chain in cerebrospinal fluid (CSF). Laminin alpha 2 chain was detected as a minor component of the total CSF proteins or glycoproteins. Laminin alpha 2 chain was localized in the cytoplasm of epithelial cells of choroid plexus, suggesting active secretion. Our results suggest that immunochemical analysis of CSF laminin alpha 2 chain could be useful as an aid for the diagnosis of congenital muscular dystrophy.
    FEBS Letters 12/1995; 376(1-2):37-40. · 3.58 Impact Factor
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    ABSTRACT: The absence of laminin α2 chain causes muscle cell degeneration and peripheral dysmyelination in congenital muscular dystrophy patients and dy mice, suggesting its role in the maintenance of sarcolemmal architecture and peripheral myelinogenesis. Here we demonstrate the secretion of laminin α2 chain in cerebrospinal fluid (CSF). Laminin α2 chain was detected as a minor component of the total CSF proteins or glycoproteins. Laminin α2 chain was localized in the cytoplasm of epithelial cells of choroid plexus, suggesting active secretion. Our results suggest that immunochemical analysis of CSF laminin α2 chain could be useful as an aid for the diagnosis of congenital muscular dystrophy.
    FEBS Letters 01/1995; 376(1):37-40. · 3.58 Impact Factor