Abstract
Sandhoff disease (SD) is caused by the loss of β-hexosaminidase (Hex) enzymatic activity in lysosomes resulting from Hexb mutations. In SD patients, the Hex substrate GM2 ganglioside accumulates abnormally in neuronal cells, resulting in neuronal loss, microglial activation, and astrogliosis. Hexb(-/-) mice, which manifest a phenotype similar to SD, serve as animal models for examining the pathophysiology of SD. Hexb(-/-) mice reach ~8 weeks without obvious neurological defects; however, trembling begins at 12 weeks and is accompanied by startle reactions and increased limb tone. These symptoms gradually become severe by 16-18 weeks. Immune reactions caused by autoantibodies have been recently associated with the pathology of SD. The inhibition of immune activation may represent a novel therapeutic target for SD. Herein, SD mice (Hexb(-/-)) were crossed to mice lacking an activating immune receptor (FcRγ(-/-)) to elucidate the potential relationship between immune responses activated through SD autoantibodies and astrogliosis. Microglial activation and astrogliosis were observed in cortices of Hexb(-/-) mice during the asymptomatic phase, and were inhibited in Hexb(-/-) FcRγ(-/-) mice. Moreover, early astrogliosis and impaired motor coordination in Hexb(-/-) mice could be ameliorated by immunosuppressants, such as FTY720. Our findings demonstrate the importance of early treatment and the therapeutic effectiveness of immunosuppression in SD.