title: Development of a Rab9 transgenic mouse and its ability to increase the lifespan of a murine model of Niemann-Pick type C disease.
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 approximately 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 GM(2) and GM(3) 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Thoracic Diseases Research Unit, Mayo Clinic College of Medicine, Rochester, Minnesota 55905-0001, USA.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Kaptzan
authors.forename: Sally A
authors.initials: SA
authors.lastname: West
authors.forename: Eileen L
authors.initials: EL
authors.lastname: Holicky
authors.forename: Christine L
authors.initials: CL
authors.lastname: Wheatley
authors.forename: David L
authors.initials: DL
authors.lastname: Marks
authors.forename: Tengke
authors.initials: T
authors.lastname: Wang
authors.forename: Kyle B
authors.initials: KB
authors.lastname: Peake
authors.forename: Jean
authors.initials: J
authors.lastname: Vance
authors.forename: Steven U
authors.initials: SU
authors.lastname: Walkley
authors.forename: Richard E
authors.initials: RE
authors.lastname: Pagano
mesh_terms: D000818:Animals; D015153:Blotting, Western; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D052556:Niemann-Pick Disease, Type C / Q000235:genetics* / Q000503:physiopathology; D020691:rab GTP-Binding Proteins / Q000235:genetics*
chemical_list: C079856:RAB9A protein, human; D020691:rab GTP-Binding Proteins