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Originally published online as doi:10.2353/ajpath.2009.080660 on December 4, 2008

Published online before print December 4, 2008
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(American Journal of Pathology. 2009;174:14-20.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080660

Short Communication

Development of a Rab9 Transgenic Mouse and Its Ability to Increase the Lifespan of a Murine Model of Niemann-Pick Type C Disease

Tatiana Kaptzan*, Sally A. West*, Eileen L. Holicky*, Christine L. Wheatley*, David L. Marks*, Tengke Wang*, Kyle B. Peake{dagger}, Jean Vance{dagger}, Steven U. Walkley{ddagger} and Richard E. Pagano*

From the Department of Biochemistry and Molecular Biology,* Thoracic Diseases Research Unit, Mayo Clinic College of Medicine, Rochester, Minnesota; the Group on Molecular and Cell Biology of Lipids,{dagger} Department of Medicine, University of Alberta, Edmonton, Canada; and the Department of Neuroscience,{ddagger} Albert Einstein College of Medicine, Bronx, New York

Niemann-Pick, type C (NP-C) disease is an autosomal recessive neurovisceral storage disorder in which cholesterol and sphingolipids accumulate. There is no specific treatment for this disease, which is characterized by progressive neurological deterioration, sometimes accompanied by hepatosplenomegaly. We and others have shown that overexpression of certain Rab GTPases corrects defective membrane trafficking and reduces lipid storage in cultured NP-C fibroblasts. Here, we tested the possibility that Rab protein overexpression might also have beneficial effects in vivo using a murine model of NP-C. We first generated several lines of transgenic mice that ubiquitously overexpress Rab9 up to ~30-fold more than endogenous levels and found that the transgene expression had no obvious effects on fertility, behavior, or lifespan in normal mice. These transgenic strains were then crossed with NP-C mutant mice to produce NP-C homozygous recessive mice with and without the Rab9 transgene. Life expectancy of the NPC1 homozygous recessive animals was extended up to 22% depending on gender and the transgenic strain that was used. Histological studies and lipid analysis of brain sections indicated that the NP-C mice carrying the Rab9 transgene had dramatically reduced storage of GM2 and GM3 gangliosides relative to NP-C animals lacking the transgene. These results demonstrate that Rab9 overexpression has the potential to reduce stored lipids and prolong lifespan in vivo.






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