Fig. 4: Retromer stabilization by R55 or OXR1 overexpression preserves vision and rescues tauopathy-related dysfunction.
From: OXR1 maintains the retromer to delay brain aging under dietary restriction
a Flies with RU486-induced neuronal mtdRNAi in adulthood show reduced responsiveness to light. n = minimum 50 flies per replicate across 4 independent experiments. Data represent mean value across replicates +/- SD. b, Flies with constitutively active pan-neuronal mtdRNAi in development have disordered eye ommatidia. Image quantification on right. n = eyes from minimum 11 fly heads per condition. Error bars represent mean value across replicates +/- SD. c Negative geotaxis is unaffected in flies with RU486-inducible neuronal mtdRNAi. n = at least 50 flies across 2 independent experiments. Data represent mean value across replicates +/- SD. d Flies with RU486-inducible pan-neuronal overexpression of human OXR1 in adulthood have improved phototaxis throughout the lifespan. n = at least 50 flies across 3 independent experiments. Data represent mean value across replicates +/- SD. e Overexpression of vps26 or vps35 rescues loss of phototaxis in flies with constitutively active neuronal mtdRNAi. Dashed lines = mtdRNAi, dashed with solid circles = mtdRNAi with vps26OE, dashed with open circles = mtdRNAi with vps35OE. AL shown on left (red) and DR shown on right (blue). n = minimum 50 flies (except for mtdRNAi due to larval lethality) per condition across 3 independent experiments. Data represent mean value across replicates +/- SD. f Supplementation with 6 μM R55 rescues loss of phototaxis in flies with constitutively active neuronal mtdRNAi. n = minimum 50 flies (except for mtdRNAi due to larval lethality) per condition across 3 independent experiments. Data represent mean value across replicates +/- SD. g TUNEL stain for degeneration in aged fly brains is increased with RU486-inducible neuronal mtdRNAi (top row) but rescued by overexpression of vps26 (middle row) or vps35 (bottom row). Flies were raised for 21 days under AL or DR with RU486 or vehicle control prior to sample collection. Quantification on right. n = minimum 17 fly brains per condition. Error bars represent mean value across replicates +/- SD. h Venn diagram demonstrating number of genes downregulated in GTEx dataset and proteins positively correlated with OXR1 from AMP-AD dataset. Overlap in the middle. Significance determined by Fisher Exact test. i Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease are the most enriched diseases associated with the overlapping genes in h. p value adjusted for multiple testing. j, Correlation of OXR1 protein abundance with AD diagnosis (left), CERAD score (middle), and BRAAK score (right). Asymp = asymptomatic AD. n = 453 human brains. Box plots represent the median, 25th, and 75th percentiles and whiskers represent the 5th and 95th percentiles. k, Constitutively active neuronal overexpression of human OXR1 or vps35 rescues degeneration induced by expression of mutant Tau driven in the fly eye with GMR promoter. Quantification of degenerative phenotype on right. n = eyes from minimum 11 fly heads per condition. Error bars represent mean value across replicates +/- SD. For all figures, *p < 0.05, **p < 0.005, ***p < 0.0005. Except where noted, all p values were calculated by two-sided t-test.
