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ID 115018
著者
Kitakaze, Keisuke Tokushima University
Tasaki, Chikako Tokushima University
Tajima, Youichi Tokyo Metropolitan Institute of Medical Science
Hirokawa, Takatsugu National Institute of Advanced Industrial Science and Technology
Sakuraba, Hitoshi Meiji Pharmaceutical University
キーワード
Lysosomal storage disease
Gm2 gangliosidosis
Gm2 activator protein
β-hexosaminidase
Enzyme replacement therapy
資料タイプ
学術雑誌論文
抄録
GM2 gangliosidoses are autosomal recessive lysosomal storage diseases (LSDs) caused by mutations in the HEXA, HEXB and GM2A genes, which encode the human lysosomal β-hexosaminidase (Hex) α- and β-subunits, and GM2 activator protein (GM2A), respectively. These diseases are associated with excessive accumulation of GM2 ganglioside (GM2) in the brains of patients with neurological symptoms. Here we established a CHO cell line overexpressing human GM2A, and purified GM2A from the conditioned medium, which was taken up by fibroblasts derived from a patient with GM2A deficiency, and had the therapeutic effects of reducing the GM2 accumulated in fibroblasts when added to the culture medium. We also demonstrated for the first time that recombinant GM2A could enhance the replacement effect of human modified HexB (modB) with GM2-degrading activity, which is composed of homodimeric altered β-subunits containing a partial amino acid sequence of the α-subunit, including the GSEP loop necessary for binding to GM2A, on reduction of the GM2 accumulated in fibroblasts derived from a patient with Tay-Sachs disease, a HexA (αβ heterodimer) deficiency, caused by HEXA mutations. We predicted the same manner of binding of GM2A to the GSEP loop located in the modified HexB β-subunit to that in the native HexA α-subunit on the basis of the x-ray crystal structures. These findings suggest the effectiveness of combinational replacement therapy involving the human modified HexB and GM2A for GM2 gangliosidoses.
掲載誌名
Biochemistry and Biophysics Reports
ISSN
24055808
出版者
Elsevier
7
開始ページ
157
終了ページ
163
発行日
2016-06-08
権利情報
© 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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言語
eng
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出版社版
部局
薬学系