Fig. 8
ACY-738 reinstates metabolic homeostasis in the spinal cord of Tg FUS+/+ mice. a Quantitative PCR analysis of mRNA expression levels of metabolic genes in the spinal cord of P25, P30, P40 and P60 vehicle-treated Tg FUS+/+ mice and non-Tg controls, and in P60 ACY-738-treated Tg FUS+/+ mice, with Ap3b1 and Mon2 as reference genes and normalization to non-Tg controls. n = 6, Student’s t-test with Holm-Sidak method to correct for multiple testing at P25, P30 and P40 and One-way ANOVA at P60. Pentose phosphate pathway (PPP), Hexokinase 2 (Hk2), pyruvate dehydrogenase kinase 4 (Pdk4), Acyl-CoA synthetase long-chain family member 6 (Acsl6), acyl-CoA dehydrogenase family member 11 (Acad11), 3-oxoacid CoA-transferase (Oxct1), 7-Dehydrocholesterol reductase (7-Dhcr), squalene epoxidase (Sqle), Elongation of very long chain fatty acids protein 7 (Elovl7), 1-acylglycerol-3-phosphate O-acyltransferase 4 (Agpat4), Apolipoprotein D (Apod), Apolipoprotein E (Apoe), Fatty acid binding protein 4 (Fabp4). Fold change compared to non-Tg controls (FC). b Metabolite levels of glycolysis intermediates in the spinal cord of P60 non-Tg controls, vehicle- and ACY-738-treated Tg FUS+/+ mice normalized to non-Tg controls. n = 3, Two-way ANOVA with Tukey’s multiple comparisons test. Glucose-6-phosphate (glucose6P), fructose-6-phosphate (fructose6P), fructose-1,6-biphosphate (fructose1,6BP), glyceraldehyde-3-phosphate (GA3P), dihydroxyacetone phosphate (DHAP), 3-phosphoglycate (3PG), phosphoenolpyruvate (PEP). c Metabolite levels of pentose phosphate pathway intermediates in the spinal cord of P60 non-Tg controls, vehicle- and ACY-738-treated Tg FUS+/+ mice normalized to non-Tg controls. n = 3, Two-way ANOVA with Tukey’s multiple comparisons test. Ribulose-5-phosphate (ribulose5P), ribose-5-phosphate (ribose5P), sedoheptulose-7-phosphate (sedohept7P), erythrose-4-phosphate (erythrose4P). d Schematic representation of our results indicating ACY-738 therapy restores histone acetylation and FUS accumulation in the cytoplasm in transgenic mice overexpressing wild-type FUS, thereby partially restoring transcriptional defects and improving the ALS phenotype. *P < 0.05, **P < 0.01, ***P < 0.001 ****P < 0.0001. Data are presented as means ± SEM