Imbalance in Redox Homeostasis is Associated with Neurodegeneration in the Murine Model of Tay-Sachs Disease

Background Tay-Sachs disease is a type of neurodegenerative disorder with a build-up of GM2 ganglioside in the brain, which results in progressive central nervous system dysfunction. Our group recently generated Hexa-/-Neu3-/- mice, a murine model with neuropathological abnormalities similar to the infantile form of Tay-Sachs disease. Previously, we reported progressive neurodegeneration with neuronal loss in the brain sections of Hexa-/-Neu3-/- mice. However, the relationship of the severity of neurodegeneration to imbalance in redox homeostasis has not been clarified in Hexa-/-Neu3-/- mice. Here, we evaluated whether neurodegeneration is associated with oxidative stress in the tissues and cells of Hexa-/-Neu3-/- mice and neuroglia cells from Tay-Sachs patients. Methods and Results In four brain regions and fibroblasts of 5-month-old WT , Hexa-/- , Neu3-/- , and Hexa-/-Neu3-/- mice and human neuroglia cells, apoptosis and oxidative stress-related markers were evaluated using Western blot, RT-PCR, and immunohistochemistry analyses. We further analyzed oxidative stress levels using flow cytometry analyses. We discovered neuronal death, alterations in intracellular ROS levels, and damaging effects of oxidative stress, especially in the cerebellum and fibroblasts of Hexa-/-Neu3-/- mice. Conclusions Our results showed that alteration in redox homeostasis might be related to neurodegeneration in the murine model of Tay-Sachs Disease. These findings suggest that targeting the altered redox balance and increased oxidative stress might be a rational therapeutic approach for alleviating neurodegeneration and treating Tay-Sachs disease.