Inefficiency in GM2 Ganglioside Elimination by Human Lysosomal β-Hexosaminidase β-Subunit Gene Transfer to Fibroblastic Cell Line Derived from Sandhoff Disease Model Mice(Biochemistry)

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概要

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• Sandhoff disease (SD) is an autosomal recessive GM2 gangliosidosis caused by the defect of lysosomal β-hexosaminidase (Hex) β-subunit gene associated with neurosomatic manifestations. Therapeutic effects of Hex subunit gene transduction have been examined on Sandhoff disease model mice (SD mice) produced by the allelic disruption of Hexb gene encoding the murine β-subunit. We demonstrate here that elimination of GM2 ganglioside (GM2) accumulated in the fibroblastic cell line derived from SD mice (FSD) did not occur when the HEXB gene only was transfected. In contrast, a significant increase in the HexB (ββhomodimer) activity toward neutral substrates, including GA2 (asialo-GM2) and oligosaccharides carrying the terminal N-acetylglucosamine residues at their non-reducing ends (GlcNAc-oligosaccharides) was observed. Immunoblotting with anti-human HexA (αβheterodimer) serum after native polyacrylamide gel electrophoresis (Native-PAGE) revealed that the human HEXB gene product could hardly form the chimeric HexA through associating with the murine α-subunit. However, co-introduction of the HEXA encoding the human α-subunit and HEXB genes caused significant corrective effect on the GM2 degradation by producing the human HexA. These results indicate that the recombinant human HexA could interspeciesly associate with the murine GM2 activator protein to degrade GM2 accumulated in the FSD cells. Thus, therapeutic effects of the recombinant human HexA isozyme but not human HEXB gene product could be evaluated by using the SD mice.

• 2006-08-01

著者

• Tsuji Daisuke

  Department Of Medicinal Biotechnology Institute For Medicinal Resources Graduate School Of Pharmaceu

• Yamanaka Shoji

  Division Of Anatomic And Surgical Pathology Hospital Of Yokohama City University School Of Medicine

• Itoh Kohji

  Department Of Biology Chiba University

• Sakuraba Hitoshi

  Department Of Analytical Biochemistry Meiji Pharmaceutical University

• Yamanaka Shoji

  Division Of Anatomic And Surgical Pathology Hospital Of Yokohama City University

• Ishibashi Yasuhiro

  Department Of Medicinal Biotechnology Institute For Medicinal Resources Graduate School Of Pharmaceu

• Sakuraba Hitoshi

  Department Of Clinical Genetics The Tokyo Metropolitan Institute Of Medical Science Tokyo Metropolit

• ITAKURA Tomohiro

  Department of Medicinal Biotechnology, Institute for Medicinal Resources, Graduate School of Pharmac

• KUROKI Aya

  Department of Medicinal Biotechnology, Institute for Medicinal Resources, Graduate School of Pharmac

• KAWASHITA Eri

  Department of Medicinal Biotechnology, Institute for Medicinal Resources, Graduate School of Pharmac

• HIGASHINE Yukari

  Department of Medicinal Biotechnology, Institute for Medicinal Resources, Graduate School of Pharmac

• Kuroki Aya

  Department Of Medicinal Biotechnology Institute For Medicinal Resources Graduate School Of Pharmaceu

• Kawashita Eri

  Department Of Medicinal Biotechnology Institute For Medicinal Resources Graduate School Of Pharmaceu

• Itoh Kohji

  Department Of Medicinal Biotechnology Institute For Medicinal Resources Graduate School Of Pharmaceu

• Itoh Kohji

  Department Of Applied Electronics Science University Of Tokyo

• Itakura Tomohiro

  Department Of Medicinal Biotechnology Institute For Medicinal Resources Graduate School Of Pharmaceu

• Higashine Yukari

  Department Of Medicinal Biotechnology Institute For Medicinal Resources Graduate School Of Pharmaceu

• Ishibashi Yasuhiro

  Department of Internal Medicine, Iwate Medical University

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