Isofagomine in vivo effects in a neuronopathic Gaucher disease mouse.

The pharmacological chaperone, isofagomine (IFG), enhances acid β-glucosidase (GCase) function by altering folding, trafficking, and activity in wild-type and Gaucher disease fibroblasts. The in vivo effects of IFG on GCase activity, its substrate levels, and phenotype were evaluated using a neurono...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Ying Sun, Huimin Ran, Benjamin Liou, Brian Quinn, Matt Zamzow, Wujuan Zhang, Jacek Bielawski, Kazuyuki Kitatani, Kenneth D R Setchell, Yusuf A Hannun, Gregory A Grabowski
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/07efa194c76b48e6828757b10303fbfd
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:07efa194c76b48e6828757b10303fbfd
record_format	dspace
spelling	oai:doaj.org-article:07efa194c76b48e6828757b10303fbfd2021-11-18T06:55:27ZIsofagomine in vivo effects in a neuronopathic Gaucher disease mouse.1932-620310.1371/journal.pone.0019037https://doaj.org/article/07efa194c76b48e6828757b10303fbfd2011-04-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21533102/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203The pharmacological chaperone, isofagomine (IFG), enhances acid β-glucosidase (GCase) function by altering folding, trafficking, and activity in wild-type and Gaucher disease fibroblasts. The in vivo effects of IFG on GCase activity, its substrate levels, and phenotype were evaluated using a neuronopathic Gaucher disease mouse model, 4L;C* (V394L/V394L + saposin C-/-) that has CNS accumulation of glucosylceramide (GC) and glucosylsphingosine (GS) as well as progressive neurological deterioration. IFG administration to 4L;C* mice at 20 or 600 mg/kg/day resulted in life span extensions of 10 or 20 days, respectively, and increases in GCase activity and protein levels in the brain and visceral tissues. Cerebral cortical GC and GS levels showed no significant reductions with IFG treatment. Increases of GC or GS levels were detected in the visceral tissues of IFG treated (600 mg/kg/day) mice. The attenuations of brain proinflammatory responses in the treated mice were evidenced by reductions in astrogliosis and microglial cell activation, and decreased p38 phosphorylation and TNFα levels. Terminally, axonal degeneration was present in the brain and spinal cord from untreated and treated 4L;C* mice. These data demonstrate that IFG exerts in vivo effects by enhancing V394L GCase protein and activity levels, and in mediating suppression of proinflammation, which led to delayed onset of neurological disease and extension of the life span of 4L;C* mice. However, this was not correlated with a reduction in the accumulation of lipid substrates.Ying SunHuimin RanBenjamin LiouBrian QuinnMatt ZamzowWujuan ZhangJacek BielawskiKazuyuki KitataniKenneth D R SetchellYusuf A HannunGregory A GrabowskiPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 4, p e19037 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ying Sun Huimin Ran Benjamin Liou Brian Quinn Matt Zamzow Wujuan Zhang Jacek Bielawski Kazuyuki Kitatani Kenneth D R Setchell Yusuf A Hannun Gregory A Grabowski Isofagomine in vivo effects in a neuronopathic Gaucher disease mouse.
description	The pharmacological chaperone, isofagomine (IFG), enhances acid β-glucosidase (GCase) function by altering folding, trafficking, and activity in wild-type and Gaucher disease fibroblasts. The in vivo effects of IFG on GCase activity, its substrate levels, and phenotype were evaluated using a neuronopathic Gaucher disease mouse model, 4L;C* (V394L/V394L + saposin C-/-) that has CNS accumulation of glucosylceramide (GC) and glucosylsphingosine (GS) as well as progressive neurological deterioration. IFG administration to 4L;C* mice at 20 or 600 mg/kg/day resulted in life span extensions of 10 or 20 days, respectively, and increases in GCase activity and protein levels in the brain and visceral tissues. Cerebral cortical GC and GS levels showed no significant reductions with IFG treatment. Increases of GC or GS levels were detected in the visceral tissues of IFG treated (600 mg/kg/day) mice. The attenuations of brain proinflammatory responses in the treated mice were evidenced by reductions in astrogliosis and microglial cell activation, and decreased p38 phosphorylation and TNFα levels. Terminally, axonal degeneration was present in the brain and spinal cord from untreated and treated 4L;C* mice. These data demonstrate that IFG exerts in vivo effects by enhancing V394L GCase protein and activity levels, and in mediating suppression of proinflammation, which led to delayed onset of neurological disease and extension of the life span of 4L;C* mice. However, this was not correlated with a reduction in the accumulation of lipid substrates.
format	article
author	Ying Sun Huimin Ran Benjamin Liou Brian Quinn Matt Zamzow Wujuan Zhang Jacek Bielawski Kazuyuki Kitatani Kenneth D R Setchell Yusuf A Hannun Gregory A Grabowski
author_facet	Ying Sun Huimin Ran Benjamin Liou Brian Quinn Matt Zamzow Wujuan Zhang Jacek Bielawski Kazuyuki Kitatani Kenneth D R Setchell Yusuf A Hannun Gregory A Grabowski
author_sort	Ying Sun
title	Isofagomine in vivo effects in a neuronopathic Gaucher disease mouse.
title_short	Isofagomine in vivo effects in a neuronopathic Gaucher disease mouse.
title_full	Isofagomine in vivo effects in a neuronopathic Gaucher disease mouse.
title_fullStr	Isofagomine in vivo effects in a neuronopathic Gaucher disease mouse.
title_full_unstemmed	Isofagomine in vivo effects in a neuronopathic Gaucher disease mouse.
title_sort	isofagomine in vivo effects in a neuronopathic gaucher disease mouse.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/07efa194c76b48e6828757b10303fbfd
work_keys_str_mv	AT yingsun isofagomineinvivoeffectsinaneuronopathicgaucherdiseasemouse AT huiminran isofagomineinvivoeffectsinaneuronopathicgaucherdiseasemouse AT benjaminliou isofagomineinvivoeffectsinaneuronopathicgaucherdiseasemouse AT brianquinn isofagomineinvivoeffectsinaneuronopathicgaucherdiseasemouse AT mattzamzow isofagomineinvivoeffectsinaneuronopathicgaucherdiseasemouse AT wujuanzhang isofagomineinvivoeffectsinaneuronopathicgaucherdiseasemouse AT jacekbielawski isofagomineinvivoeffectsinaneuronopathicgaucherdiseasemouse AT kazuyukikitatani isofagomineinvivoeffectsinaneuronopathicgaucherdiseasemouse AT kennethdrsetchell isofagomineinvivoeffectsinaneuronopathicgaucherdiseasemouse AT yusufahannun isofagomineinvivoeffectsinaneuronopathicgaucherdiseasemouse AT gregoryagrabowski isofagomineinvivoeffectsinaneuronopathicgaucherdiseasemouse
_version_	1718424147655131136

Isofagomine in vivo effects in a neuronopathic Gaucher disease mouse.

Ejemplares similares