Imbalance in redox homeostasis is associated with neurodegeneration in the murine model of Tay-Sachs disease.

Abstract

Background: Tay-Sachs disease is a neurodegenerative disorder characterized by 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 between the severity of neurodegeneration and the imbalance in redox homeostasis was not yet 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: Cell death and oxidative stress-related markers were evaluated in four brain regions and fibroblasts of 5-month-old WT, Hexa-/-, Neu3-/-, and Hexa-/-Neu3-/- mice and human neuroglia cells using Western blot, RT-PCR, and immunohistochemistry analyses. We further analyzed oxidative stress levels in the samples 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.