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Journal of Lipid Research, Vol. 47, 2161-2170, October 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Conditional expression of human acid ß-glucosidase improves the visceral phenotype in a Gaucher disease mouse model

Ying Sun^*, Brian Quinn^*, You-Hai Xu^*, Tatyana Leonova¹, David P. Witte and Gregory A. Grabowski^2,*

^* Division of Human Genetics, Children's Hospital Research Foundation and University of Cincinnati College of Medicine, Department of Pediatrics, Cincinnati, OH 45229-3039
Division of Pediatric Pathology, Children's Hospital Research Foundation and University of Cincinnati College of Medicine, Department of Pediatrics, Cincinnati, OH 45229-3039

Published, JLR Papers in Press, July 21, 2006.

¹ Present address of T. Leonova: Laboratory of Lymphocyte Biology, Rockefeller University, New York, NY 10021.

² To whom correspondence should be addressed. e-mail: greg.grabowski{at}cchmc.org

The reversibility and regression of histological and biochemical findings in a mouse model of Gaucher disease (4L/PS-NA) was evaluated using a liver-enriched activator protein promoter control of a tetracycline-controlled transcriptional activation-responsive human acid ß-glucosidase (hGCase) transgenic system. 4L/PS-NA has the acid ß-glucosidase (GCase) V394L/V394L (4L) point mutation combined with hypomorphic (6% wild-type) expression of the mouse prosaposin transgene (PS-NA). The hGCase/4L/PS-NA had exclusive liver expression of hGCase controlled by doxycycline (DOX). In the absence of DOX, hGCase was secreted from liver at levels of 120 µg/ml serum with only 8% of full activity, following exposure to pH 7.4 in serum. The hGCase activity and protein were detected in cells of the liver (massive), lung, and spleen, but not the brain. The visceral tissue storage cells and glucosylceramide (GC) accumulation in hGCase/4L/PS-NA were decreased from that in 4L/PS-NA mice. Turning off hGCase expression with dietary DOX led to reaccumulation of storage cells and of GC in liver, lung, and spleen, and macrophage activation in those tissues. This study demonstrates that conditionally expressed hGCase supplemented the existing mutant mouse GCase to control visceral substrate accumulation in vivo.

Abbreviations: CNS, central nervous system; CRIM, cross-reacting immunological material; DOX, doxycycline; GC, glucosylceramide; GCase, acid ß-glucosidase; hGCase, human acid ß-glucosidase; LAP, liver-enriched activator protein; SA, specific activity; tTA, tetracycline-controlled transcriptional activation; WT, wild type

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