Abstract
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 beta-glucosidase (hGCase) transgenic system. 4L/PS-NA has the acid beta-glucosidase (GCase) V394L/V394L (4L) point mutation combined with hypomorphic ( approximately 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 approximately 120 microg/ml serum with only approximately 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.
Highlights
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 b-glucosidase transgenic system. 4L/PS-NA has the acid b-glucosidase (GCase) V394L/V394L (4L) point mutation combined with hypomorphic (z6% wild-type) expression of the mouse prosaposin transgene (PS-NA)
Generating hG/4L/PS-NA mice. hG/4L/PS-NA mice were generated by breeding 4L/PS-NA (PS-NA; V394L/V394L) (19) mice with mice containing a 2.9 kb transgene fragment of the liverenriched activator protein (LAP) promoter and transcriptional activation (tTA) gene (22)
4L/PS-NA mice were generated by crossing 4L homozygous mice with those bearing a hypomorphic prosaposin transgene (PS-NA) (19)
Summary
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 b-glucosidase (hGCase) transgenic system. 4L/PS-NA has the acid b-glucosidase (GCase) V394L/V394L (4L) point mutation combined with hypomorphic (z6% wild-type) expression of the mouse prosaposin transgene (PS-NA). 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. Conditional expression of human acid b-glucosidase improves the visceral phenotype in a Gaucher disease mouse model. The partial deficiency of saposins led to decreased stability of the mutant GCase to proteolysis and subsequent additional decreases in V394L GCase activity This model mimics a more severe Gaucher disease phenotype and is a Abbreviations: CNS, central nervous system; CRIM, cross-reacting immunological material; DOX, doxycycline; GC, glucosylceramide; GCase, acid b-glucosidase; hGCase, human acid b-glucosidase; LAP, liver-enriched activator protein; SA, specific activity; tTA, tetracyclinecontrolled transcriptional activation; WT, wild type. This article is available online at http://www.jlr.org
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