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.

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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 The American Journal of Pathology Volume 174, Issue 1, Pages 14-20 (January 2009) DOI: 10.2353/ajpath.2009.080660 Copyright © 2009 American Society for Investigative Pathology Terms and Conditions

Figure 1 Expression of the Rab9 transgene in founder mice and in Rab9TG+/− NPCmut/mut mice. A and B: Brain and liver samples from founder and NPCmut/mut animals from each of the Rab9 transgenic strains at 6 weeks of age were harvested and blotted with an antibody that recognizes both the HA-tagged human Rab9, and endogenous mouse Rab9. Five μg of protein per lane were used to visualize the HA-tagged Rab9 transgene, whereas 20 μg of protein per lane were required for reliable detection of endogenous Rab9 (see Materials and Methods for details). Samples were also blotted for β-actin to demonstrate equal loading. B: Bar graphs show the Rab9 transgene levels for transgenic founders (n = 3) and Rab9TG+/− NPCmut/mut (n = 3) mice (age, 10 weeks) in brain (red) relative to the signal for endogenous Rab9 in the liver (green). C: Western blotting for Rab9 of liver and brain homogenates (5 μg) from 4-week-old Rab9TG+/− NPCWT/WT and Rab9TG+/− NPCmut/mut mice (strain 500), as well as Rab9TG− controls (20 μg). D: Immunostaining of the Rab9 transgene in the brain of NPCmut/mut animals at 7 weeks. Left: Brain sections from 50-day-old animals of the indicated genotypes were stained with a rat anti-HA Ab to detect the Rab9 transgene. Brown staining indicates the presence of the expressed Rab9 transgene. Right: Enlargement of the cerebellum from the left panel. Left (low mag) panels in D, ×2.3. Right (high mag) panels in D, ×7. The American Journal of Pathology 2009 174, 14-20DOI: (10.2353/ajpath.2009.080660) Copyright © 2009 American Society for Investigative Pathology Terms and Conditions

Figure 2 Effect of Rab9 overexpression on symptoms of NP-C mice. A: Retardation of weight loss. Male mice obtained from crosses of NP-C mice with Rab9 transgenic mice (strain 500) were weighed weekly. NPCmut/mut animals began to lose weight at weeks 6 to 7, whereas the presence of the Rab9 transgene retarded the weight loss. n = 5, 10, and 7 for Rab9TG− NPCWT/WT, Rab9TG+ NPCmut/mut, and Rab9TG− NPCmut/mut mice, respectively. Values were significantly different in two-tailed t-tests (P < 0.0 5) between Rab9TG+ NPCmut/mut and Rab9TG− NPCmut/mut mice at all points after 4 weeks. Similar results were obtained using the other transgenic strains and are shown in Supplemental Figure S2 at http://ajp.amjpathol.org. B and C: Rab9 transgene expression reduces ganglioside accumulation in the brain. Representative examples of cortex from normal, Rab9TG− NPCmut/mut, and Rab9TG+ NPCmut/mut mice immunostained for GM2 and GM3 gangliosides are shown in B. Note the reduction in ganglioside staining in NPCmut/mut mice expressing the Rab9 transgene. Two additional experiments gave similar results (data not shown). Similar results to those shown in B were also obtained using NPCmut/mut mice expressing the Rab9TG from founder strain 800 (see Supplemental Figure S3 at http://ajp.amjpathol.org). Original magnification: ×35. C: Gangliosides were extracted from 80-day-old NPCmut/mut mice ± Rab9 transgene (strain 500), separated by thin-layer chromatography, and quantified by image analysis after staining the gangliosides with resorcinol.6 Bar graph shows the reduction in GM3 (45%) and GM2 (32%) levels in NPCmut/mut mice expressing the Rab9 transgene, relative to the levels of GM3 and GM2 in control, NPCmut/mut mice without the transgene. Values are the mean of two experiments. The American Journal of Pathology 2009 174, 14-20DOI: (10.2353/ajpath.2009.080660) Copyright © 2009 American Society for Investigative Pathology Terms and Conditions

Figure 3 Effect of Rab9 overexpression on lifespan of NP-C mice. A: Kaplan-Meier survival plots for NPCmut/mut mice without or with expression of the Rab9 (strain 500) transgene (P < 0.0001). Kaplan-Meier plots for other strains are shown in Supplemental Figure S4 at http://ajp.amjpathol.org. B: Bar graphs showing percent increase in lifespan based on the difference in lifespan of NPCmut/mut animals ± Rab9TG expression. All values were significant except for strain 400. Student's t-test was used for calculating statistical significance. n values for each group are as follows: all animals, Rab9TG+ = 28, Rab9TG− = 31; females, Rab9TG+ = 11, Rab9TG− = 21; males, Rab9TG+ = 17, Rab9TG− = 10. The American Journal of Pathology 2009 174, 14-20DOI: (10.2353/ajpath.2009.080660) Copyright © 2009 American Society for Investigative Pathology Terms and Conditions