Fig. 9

Treatment with LXR-receptor agonists improves locomotor behaviour in Arl6IP1 KO models of SGP61. a Graph represent mean ± SEM percentage of CRISPR Control or Arl6IP1 KO flies that reach the top of the vial within 15 s. n = 10–16 independent experiments per genotype. Statistics consists of two-way ANOVA and Bonferroni’s multiple comparisons tests. b and c Proposed model for ARL6IP1 function in lipid homeostasis within axon bundles. b In wildtype systems, lipids required by neurons are stored in glia and then transferred into neurons when needed. The ER functions to regulate lipid homeostasis via ER-localised lipid transporters and lipid metabolising enzymes. b Loss of function Arl6IP1 mutations, similar to those known to cause HSP in patients, disrupt ER organisation and lipid homeostasis resulting in LD accumulation within adjacent glia. Lipid disruption contributes to disease pathogenesis as restoration of lipid balance by treatment with LXR-agonists, which enhance cholesterol efflux from glia, reduces neurodegeneration in our fly model of HSP