出版社：American Society for Biochemistry and Molecular Biology
摘要：The reversibility and regression of histological and biochemicalfindings in a mouse model of Gaucher disease (4L/PS-NA) wasevaluated using a liver-enriched activator protein promotercontrol of a tetracycline-controlled transcriptional activation-responsivehuman 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-NAhad exclusive liver expression of hGCase controlled by doxycycline(DOX). In the absence of DOX, hGCase was secreted from liverat levels of 120 µg/ml serum with only 8% of full activity,following exposure to pH 7.4 in serum. The hGCase activity andprotein were detected in cells of the liver (massive), lung,and spleen, but not the brain. The visceral tissue storage cellsand glucosylceramide (GC) accumulation in hGCase/4L/PS-NA weredecreased from that in 4L/PS-NA mice. Turning off hGCase expressionwith dietary DOX led to reaccumulation of storage cells andof GC in liver, lung, and spleen, and macrophage activationin those tissues. This study demonstrates that conditionallyexpressed hGCase supplemented the existing mutant mouse GCaseto 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
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 
