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, Jean Vance, Steven U. Walkley, Richard E. Pagano

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)14-20
Number of pages7
JournalAmerican Journal of Pathology
Volume174
Issue number1
DOIs
StatePublished - Jan 2009

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Type C Niemann-Pick Disease
Aptitude
Transgenes
Transgenic Mice
Lipids
G(M2) Ganglioside
G(M3) Ganglioside
rab GTP-Binding Proteins
Sphingolipids
Life Expectancy
Fertility
Fibroblasts
Cholesterol
Membranes
Brain
Proteins

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Development of a Rab9 transgenic mouse and its ability to increase the lifespan of a murine model of niemann-pick type C disease. / Kaptzan, Tatiana; West, Sally A.; Holicky, Eileen L.; Wheatley, Christine L.; Marks, David L.; Wang, Tengke; Peake, Kyle B.; Vance, Jean; Walkley, Steven U.; Pagano, Richard E.

In: American Journal of Pathology, Vol. 174, No. 1, 01.2009, p. 14-20.

Research output: Contribution to journalArticle

Kaptzan, T, West, SA, Holicky, EL, Wheatley, CL, Marks, DL, Wang, T, Peake, KB, Vance, J, Walkley, SU & Pagano, RE 2009, 'Development of a Rab9 transgenic mouse and its ability to increase the lifespan of a murine model of niemann-pick type C disease', American Journal of Pathology, vol. 174, no. 1, pp. 14-20. https://doi.org/10.2353/ajpath.2009.080660
Kaptzan, Tatiana ; West, Sally A. ; Holicky, Eileen L. ; Wheatley, Christine L. ; Marks, David L. ; Wang, Tengke ; Peake, Kyle B. ; Vance, Jean ; Walkley, Steven U. ; Pagano, Richard E. / Development of a Rab9 transgenic mouse and its ability to increase the lifespan of a murine model of niemann-pick type C disease. In: American Journal of Pathology. 2009 ; Vol. 174, No. 1. pp. 14-20.
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