トクトミ　トモハル   Tomoharu Tokutomi   徳富　智明    所属   川崎医科大学  医学部 臨床医学　小児科学    職種   特任教授
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	Peracetylated N-acetylmannosamine, a synthetic sugar molecule, efficiently rescues muscle phenotype and biochemical defects in mouse model of sialic acid-deficient myopathy.
掲載誌名	正式名：The Journal of biological chemistry ISSNコード：0021-9258
掲載区分	国外
出版社	AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
巻・号・頁	287(4),pp.2689-705
著者・共著者	May Christine V Malicdan,Satoru Noguchi,Tomoharu Tokutomi,Yu-ichi Goto,Ikuya Nonaka,Yukiko K Hayashi,Ichizo Nishino
発行年月	2012/01/20
概要	Distal myopathy with rimmed vacuoles/hereditary inclusion body myopathy (DMRV/hIBM), characterized by progressive muscle atrophy, weakness, and degeneration, is due to mutations in GNE, a gene encoding a bifunctional enzyme critical in sialic acid biosynthesis. In the DMRV/hIBM mouse model, which exhibits hyposialylation in various tissues in addition to muscle atrophy, weakness, and degeneration, we recently have demonstrated that the myopathic phenotype was prevented by oral administration of N-acetylneuraminic acid, N-acetylmannosamine, and sialyllactose, underscoring the crucial role of hyposialylation in the disease pathomechanism. The choice for the preferred molecule, however, was limited probably by the complex pharmacokinetics of sialic acids and the lack of biomarkers that could clearly show dose response. To address these issues, we screened several synthetic sugar compounds that could increase sialylation more remarkably and allow demonstration of measurable effects in the DMRV/hIBM mice. In this study, we found that tetra-O-acetylated N-acetylmannosamine increased cell sialylation most efficiently, and in vivo evaluation in DMRV/hIBM mice revealed a more dramatic, measurable effect and improvement in muscle phenotype, enabling us to establish analysis of protein biomarkers that can be used for assessing response to treatment. Our results provide a proof of concept in sialic acid-related molecular therapy with synthetic monosaccharides.
DOI	10.1074/jbc.M111.297051
PMID	22157763