Increased globotriaosylceramide levels in a transgenic mouse expressing human  1,4-galactosyltransferase and a mouse model for treating Fabry disease

Shiozuka, Chikara; Taguchi, Atsumi; Matsuda, Junichiro; Noguchi, Yoko; Kunieda, Takanori; Uchio‐Yamada, Kozue; Yoshioka, Hidekatsu; Hamanaka, Ryoji; Yano, Shinji; Yokoyama, Shigeo; Mannen, Kazuaki; Kulkarni, Ashok B.; Furukawa, Koichi; Ishii, Satoshi

doi:10.1093/jb/mvq125

Cited by 18 publications

(16 citation statements)

References 28 publications

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“…Despite the signifi cant accumulation of Gb 3 and lysoGb 3 in kidney of Fabry mice shown in this study and others ( 17 ) and the pathological changes in kidney tissues ( 8,10 ), there are no obvious clinical abnormalities such as proteinuria and renal failure, which are common in Fabry patients, reported in Fabry mice. A systematic characterization …”

Section: Discussioncontrasting

confidence: 65%

Sex differences of urinary and kidney globotriaosylceramide and lyso-globotriaosylceramide in Fabry mice

Durant¹,

Forni²,

Sweetman³

et al. 2011

Journal of Lipid Research

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Section: Discussioncontrasting

confidence: 65%

Sex differences of urinary and kidney globotriaosylceramide and lyso-globotriaosylceramide in Fabry mice

Durant¹,

Forni²,

Sweetman³

et al. 2011

Journal of Lipid Research

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“…Transgenic (TgG3S) mice expressing human G3S, generated in our previous study [18], were maintained by breeding with wild-type C57BL/6 mice. The G3Stg/GLAko mouse line was generated by crossbreeding male TgG3S mice and homozygous female GLAko mice [6].…”

Section: Methodsmentioning

confidence: 99%

“…We previously generated human Gb3 synthase (G3S)-transgenic mice (TgG3S mice) with elevated Gb3 levels in major organs [18]. In this study, we prepared a new mouse line (G3Stg/GLAko) by crossbreeding TgG3S and GLAko mice to obtain a phenotypic model for Fabry disease.…”

Section: Introductionmentioning

confidence: 99%

A symptomatic Fabry disease mouse model generated by inducing globotriaosylceramide synthesis

Taguchi

Maruyama

Nameta

et al. 2013

Biochemical Journal

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Synopsis Fabry disease is a lysosomal storage disorder in which neutral glycosphingolipids, predominantly globotriaosylceramide (Gb3), accumulate due to deficient α-galactosidase A (α-Gal A) activity. The α-Gal A-knockout (GLAko) mouse has been used as a model for Fabry disease, but it does not have any symptomatic abnormalities. In this study, we generated a symptomatic mouse model (G3Stg/GLAko) by crossbreeding GLAko mice with transgenic mice expressing human Gb3 synthase. G3Stg/GLAko mice had high Gb3 levels in major organs, and their serum Gb3 level at 5–25 weeks of age was 6–10 times higher than that in GLAko mice of the same age. G3Stg/GLAko mice showed progressive renal impairment, with albuminuria at 3 weeks of age, decreased urine osmolality at 5 weeks, polyuria at 10 weeks, and increased blood urea nitrogen at 15 weeks. The urine volume and urinary albumin concentration were significantly reduced in the G3Stg/GLAko mice when human recombinant α-Gal A was administered intravenously. These data suggest that Gb3 accumulation is a primary pathogenic factor in the symptomatic phenotype of G3Stg/GLAko mice, and that this mouse line is suitable for studying the pathogenesis of Fabry disease and for preclinical studies of candidate therapies.

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“…In this study, we show the utility of pharmacoperone drugs to correct disease by rescuing PM expression rescue of a misfolded GPCR. Previous work using mouse models of lysosomal storage diseases demonstrated that pharmacoperone treatment can stabilize inactive misfolded soluble lysosomal enzymes and improve their function (18)(19)(20). These studies provided proof of principle that pharmacoperones can stabilize a misfolded protein in vivo.…”

Section: Comparison Of Gnrhr Mouse Mutants Reveals the Consequences Ofmentioning

confidence: 85%

Restoration of testis function in hypogonadotropic hypogonadal mice harboring a misfolded GnRHR mutant by pharmacoperone drug therapy

Janovick

Stewart

Jacob

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Mutations in receptors, ion channels, and enzymes are frequently recognized by the cellular quality control system as misfolded and retained in the endoplasmic reticulum (ER) or otherwise misrouted. Retention results in loss of function at the normal site of biological activity and disease. Pharmacoperones are target-specific small molecules that diffuse into cells and serve as folding templates that enable mutant proteins to pass the criteria of the quality control system and route to their physiologic site of action. Pharmacoperones of the gonadotropin releasing hormone receptor (GnRHR) have efficacy in cell culture systems, and their cellular and biochemical mechanisms of action are known. Here, we show the efficacy of a pharmacoperone drug in a small animal model, a knock-in mouse, expressing a mutant GnRHR. This recessive mutation (GnRHR E 90 K) causes hypogonadotropic hypogonadism (failed puberty associated with low or apulsatile luteinizing hormone) in both humans and in the mouse model described. We find that pulsatile pharmacoperone therapy restores E 90 K from ER retention to the plasma membrane, concurrently with responsiveness to the endogenous natural ligand, gonadotropin releasing hormone, and an agonist that is specific for the mutant. Spermatogenesis, proteins associated with steroid transport and steroidogenesis, and androgen levels were restored in mutant male mice following pharmacoperone therapy. These results show the efficacy of pharmacoperone therapy in vivo by using physiological, molecular, genetic, endocrine and biochemical markers and optimization of pulsatile administration. We expect that this newly appreciated approach of protein rescue will benefit other disorders sharing pathologies based on misrouting of misfolded protein mutants.protein trafficking | protein misrouting | intracellular trafficking

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Increased globotriaosylceramide levels in a transgenic mouse expressing human 1,4-galactosyltransferase and a mouse model for treating Fabry disease

Cited by 18 publications

References 28 publications

Sex differences of urinary and kidney globotriaosylceramide and lyso-globotriaosylceramide in Fabry mice

Sex differences of urinary and kidney globotriaosylceramide and lyso-globotriaosylceramide in Fabry mice

A symptomatic Fabry disease mouse model generated by inducing globotriaosylceramide synthesis

Restoration of testis function in hypogonadotropic hypogonadal mice harboring a misfolded GnRHR mutant by pharmacoperone drug therapy

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