Fig. 2 Spt4 modulation influences pathogenicity of GGGGCC repeats in C

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Fig. 2 Spt4 modulation influences pathogenicity of GGGGCC repeats in C Fig. 2 Spt4 modulation influences pathogenicity of GGGGCC repeats in C. elegans and mitigates neurodegeneration in a Drosophila model of c9FTD/ALS. Spt4 modulation influences pathogenicity of GGGGCC repeats in C. elegans and mitigates neurodegeneration in a Drosophila model of c9FTD/ALS. (A) RNA FISH reveals GGGGCC RNA foci formation (red) in normal (N2) worms, (GGGGCC)66-expressing worms (C9 66R), and worms expressing both (GGGGCC)66 and human SUPT4H1 (C9 66R × SUPT4H1). The intestinal marker (green) denotes the presence of the (GGGGCC)66 transgene, and DAPI (blue) indicates labeled nuclei (scale bar: low magnification 50 μm, high magnification 5 μm). (B and C) Expression of GGGGCC RNA levels quantified by qPCR relative to levels in (GGGGCC)66-expressing worms (two-tailed unpaired t test, ****P < 0.0001) (B) and poly(GP) levels quantified by immunoassay (two-tailed unpaired t test, ****P < 0.0001) (C). (D) A life-span assay assessed the impact of (GGGGCC)66 and/or SUPT4H1 overexpression on survival (N2 n = 145 worms, C9 66R n = 160, C9 66R × SUPT4H1 n = 122, SUPT4H1 n = 144; log-rank (Mantel-Cox) test, ****P < 0.0001; n.s., not significant. See also fig. S3G). (E to H) qPCR measured GGGGCC (E) and Spt4 mRNA (F) levels in (GGGGCC)66-expressing worms fed control (OP50) or RNAi targeting Spt4 (two-tailed unpaired t test, ****P < 0.0001). (G) An immunoassay revealed the percentage change in poly(GP) levels after RNAi-mediated reduction in Spt4 expression (two-tailed unpaired t test, ****P < 0.0001). (H) Spt4 RNAi improved survival in (GGGGCC)66 worms (OP50 n = 119 worms, RNAi Spt4 n = 120; log-rank (Mantel-Cox) test, ****P < 0.0001. See also fig. S3G). (I and J) External and internal retinal structures of normal flies or flies expressing (GGGGCC)n transgenes, with coexpression of (I) a control (luciferase) shRNA or (J) Spt4 shRNA. A gmr-GAL4 eye-specific driver was used to express UAS-transgenes. (I) Control animals with driver alone (w1118) or a short GGGGCC repeat (GGGGCC)6 have normal eye structure. Animals expressing GGGGCC29 show a mild disruption to the highly precise external ommatidial structure (arrows), and thinning and gaps in the internal retina, whereas animals expressing GGGGCC49 have severely degenerate tissue both externally and internally. (J) Reduction in Spt4 has no effect on normal or GGGGCC6-expressing animals and resulted in reduced toxicity in both the external and internal retinal structures of flies bearing 29 or 49 GGGGCC repeats. (K) Reducing the expression of Spt4 in (GGGGCC)49 animals increased the life expectancy for animals expressing transgenes using a ubiquitous, drug-inducible driver, da-GS. Expression was induced in adult animals to avoid effects of expressing transgenes during development. Expression of the control (luciferase) shRNA or Spt4 shRNA had no effect on the life span over this time frame when expressed alone (curves superimposed). Statistical analysis was done using a log-ranked test comparing (GGGGCC)49 animals expressing the control shRNA versus the Spt4 shRNA. Nicholas J. Kramer et al. Science 2016;353:708-712 Copyright © 2016, American Association for the Advancement of Science