Analysis of Brain Lipids in the Early-Onset Tay-Sachs Disease Mouse Model With the Combined Deficiency of β-Hexosaminidase A and Neuraminidase 3.

Tay-Sachs disease is an autosomal recessively inherited lysosomal storage disease that results from loss-of-function mutations in the gene coding β-hexosaminidase A. gene deficiency affects the central nervous system owing to GM2 ganglioside accumulation in lysosomes resulting in progressive neurodegeneration in patients. We recently generated a novel mice model with a combined deficiency of β-hexosaminidase A and neuraminidase 3 () that mimics both the neuropathological and clinical abnormalities of early-onset Tay-Sachs disease. Here, we aimed to explore the secondary accumulation of lipids in the brain of mice. In the cortex and hippocampus of five-month-old , , , and mice, lipid levels belonging to glycerolipids, glycerophospholipids, and sterol lipids were evaluated using a shotgun lipidomics approach. The levels of myelin were also assessed by luxol fast blue staining and immunohistochemistry using antibodies against myelin basic protein. We further examined glycoconjugate and cholesterol levels by periodic acid-Schiff and filipin staining, respectively. Toluidine blue staining was also performed to display axonal degeneration. Among glycerophospholipids, we demonstrated elevated levels of phosphatidylcholine-ether and lysophosphatidylcholine while decreased levels of phosphatidylcholine and phosphatidylserine in both cortex and hippocampus of mice. In the glycerolipid class, we showed an alleviated level of sphingomyelin in both cortex and hippocampus, but the higher levels of diacylglycerol and triacylglycerol were detected in only the hippocampus of mice. The lower level of sterol was also detected in the cortex of mice but not in the hippocampus. Histochemical studies showed a decrease in the myelin level and axonal degeneration indicating neuronal pathology in the brain of mice. Although glycoconjugate accumulation was evident both in the cortex and hippocampus, we did not detect any changes in the level of cholesterol. Our results indicate that alterations in lipid metabolism and neuropathology, such as demyelination and axonal degeneration, might be related to the dysfunctionality of lipid-related cellular pathways like autophagy. Understanding of brain-specific lipid alterations contributes to evaluating the effectiveness of treatments in mice in future studies.