Fig. 1: Cyclodextrin extends lifespan and reduces Neurofilament levels in female GA-Nes mice. | Nature Communications

Fig. 1: Cyclodextrin extends lifespan and reduces Neurofilament levels in female GA-Nes mice.

From: Correction of dysregulated lipid metabolism normalizes gene expression in oligodendrocytes and prolongs lifespan in female poly-GA C9orf72 mice

Fig. 1

a Gene expression changes in the cholesterol pathway from historical bulk RNAseq dataset in GA-Nes (endstage hippocampus, cortex and spinal cord, 5 control vs 5 GA-Nes mice), GA-CFP (thoracic spinal cord, cohort #1 with 4 wildtype vs. 3 GA-CFP mice 32 weeks of age, cohort #2 with 7 wildtype vs. 6 GA-CFP mice 42 weeks of age) and rNLS8 (hippocampus, after 3 weeks of transgene induction, cohort #1 with 17 wildtype vs. 10 rNLS8 mice, cohort #2 with 11 wildtype and 10 rNLS8 mice) ALS mouse models and patient spinal cord34,37,51. Log2 fold changes compared to controls are shown in the heat map. Adjusted p values from the original analysis are shown because different genotype and species prevent a combined re-analysis with common RNAseq pipelines. Asterisks indicate significant changes. Upregulation of export pathway genes and downregulation of synthesis genes suggest cholesterol overload. b Survival analysis by Kaplan–Meier curve shows that CD administered at 2 g/kg q.d. does not affect the survival of transgenic male mice significantly (p = 0.097 from log-rank test for survival, n = 12 vehicle vs 5 CD). c Survival analysis by Kaplan–Meier curve shows that CD administered at 2 g/kg q.d. significantly improves the survival of transgenic female mice (p = 0.019 from log-rank test for survival, n = 7 vehicle vs 10 CD). d, e Serum NfL from independent cohorts of mice sacrificed at postnatal day 40 (P40) shows significant modulations (female n from independent biological replicates: WT Vehicle = 4, WT CD = 7, Tg Vehicle = 4, Tg CD = 5; male n of independent biological replicates: WT Vehicle = 8, WT CD = 15, Tg Vehicle = 5, Tg CD = 9). Post-hoc analysis by Tukey’s HSD shows a dramatic increase in transgenic mice, which is partially rescued by CD treatment in female but not male mice. CD administration does not modulate wild-type NfL levels. f, g Fluorescence microscopy of endogenous GA-GFP in frozen tissue confirms its neuronal and glial expression in transgenic mice and the lack of expression in wild-type mice, while also highlighting no significant reduction upon CD treatment (ANOVA, post hoc by Tukey’s HSD from three independent biological replicates in each group). All scale bars = 75 µm.

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