engleski

Brain lipidomics of St8sia1 knockout mouse predicts neurological deficit

Introduction: Gangliosides are major constituents of plasma membrane signaling domains - lipid rafts. St8sia1 knockout mice lack b-series ganglioside synthesis (GD1b and GT1b) which is compensated by increased a-series ganglioside synthesis (GM1 and GD1a) but does not lead to changes in brain morphology. Materials and methods: MALDI-TOF-MS analysis of fresh brain tissue was performed on St8sia1 knockout (KO) mice 4.5 months old and wild-type controls (WT). To determine relevant molecular differences between the groups, the significance level was set to 0.05 and the statistical analysis was performed using ANOVA with Bonferroni correction. Succinate dehydrogenase enzyme activity was shown by histological staining. Tissue distribution of cholesterol, phospholipids, and actin was determined by fluorescent assays (TopFluor Cholesterol, Sulforhodamine, and Rhodamine Phalloidin, respectively). Histological staining was quantified using a computer program Fiji. Results: The principal component analysis of lipidomic data showed a clear separation between KO and WT - PC1 and PC2 explained 87.25% of the variability. A statistically significant downregulation in basal ganglia of KO animals was found in metabolites of the following synthetic pathways: porphyrins, ubiquinone, ferroptosis, and fat chain elongation. The sensitivity of their basal ganglia to oxidative damage and ferroptosis is further supported by the finding of reduced succinate dehydrogenase activity. Additionally, weaker cholesterol and phospholipid staining was found throughout capsula interna, nucleus caudatus and putamen of KO animals. Contrary, actin microfilament staining was significantly enhanced in examined brain regions of KO mice which could indicate amplified axon growth. Discussion and conclusion: Deficiency in ganglioside synthesis in St8sia KO mice leads to a number of metabolic adjustments. Subsequent studies should demonstrate the resistance of the oxidative-reductive balance in the basal ganglia to minor insults. Clinical aplication: Every cell in nature carries a rich surface coat of glycans, its glycocalyx. Among their functions, gangliosides regulate cell- cell interactions and modulate the activities of other cell surface molecules. Some studies have shown a strong correlation between the malignancy in mice model gliomas and the expression of the St8sia1 gene. Also, a clear correlation is seen in the role of adult brain plasticity, including regeneration, with the ganglioside composition. It is yet uncertain how this finding could benefit the standard clinical practice.

St8sia1, lipidomics, MALDI-TOF-MS, gangliosides, GD3 synthase

Support: Croatian Science Foundation under project number 2158-61- 07-14-118 and European regional development and Croatian Ministry of Science fund under project number KK.01.1.1.02.0015.