Fig. 6

Nilotinib decreases neuroinflammation in Vps13a^−/− mice. a Representative images of Iba-1 positive microglia cells in cortex of Vps13a^−/− mice treated with vehicle or with nilotinib (25 mg/kg/d for 6 months) (Microglia in red, nuclei in blue). Scale bar:50 mm. Quantitative analyses show significant differences in microglial density and activation in the cortex of Vps13a^−/− vehicle compared to treated mice. Results are expressed as mean ± SEM (*P < 0.05; ****P < 0.0001; Unpaired t-test). b Western blot (Wb) analysis of phospho-NF-kB p65 and NF-kB p65 in the cortex (left panel) and in isolated basal ganglia (right panel) from 12 and 18 months (Mo) old wild-type mice and Vps13a^−/− animals treated with vehicle or with nilotinib (25 mg/kg/d for 3 months (3Mo) and 6 months (6Mo) respectively). GAPDH was the protein loading control. Lower panel. Densitometric analyses of the immunoblot bands similar to those shown are presented. Data are means ± SEM (n = 6; ^P < 0.05 vs. 12 months old mice; °P < 0.05 vs. vehicle treated Vps13a^−/− by 2-way ANOVA with Bonferroni correction for multiple comparison). c Mice genetically lacking chorein (Vps13a^−/−) display phenotype similar to patients with chorea-acanthocytosis (ChAc). We show protein accumulation and impaired autophagy in both red cells and basal ganglia from Vps13a^−/− mice. This is associated with neuronal loss, neuroinflammation and generation of circulating acanthocytes. Tyrosine kinase inhibitors (TKI) targeting Lyn kinase have been tested in Vps13a^−/− mice. Nilotinib but not dasatinib reduces protein accumulation and ameliorates autophagy with reduction in neuronal loss and neuroinflammation as well as in circulating acanthocytes. Atgs: autophagy related proteins