Improvement in dysmyelination by the inhibition of microglial activation in a mouse model of Sandhoff disease.

Sandhoff disease (SD) is a genetic disorder caused by a mutation of the ß-subunit gene ß-hexosaminidase B (HexB) in humans, which results in the massive accumulation of the ganglioside GM2 and related glycosphingolipids in the nervous system. SD causes progressive neurodegeneration and changes in white matter in human infants. An animal model of SD has been established, Hexb-deficient (Hexb) mice, which shows abnormalities resembling the severe phenotype found in human infants. Previously, we reported that the activation state of microglia caused astrogliosis in the early stage of Hexb mouse development. To study how the symptoms of SD develop, we explored the difference in gene expression between 4-week-old Hexb and Hexb mouse cerebral cortices by microarray analysis. The data indicated not only the upregulation of immune system-related genes but also the downregulation of myelin-related genes in the 4-week-old Hexb mouse cerebral cortices. To test the correlation between inflammation and dysmyelination, we generated double-knockout mice of Hexb and the Fc receptor γ gene (Fcrγ), which is a regulator of autoimmune responses. Dysmyelination recovered in these double-knockout mice. The number of oligodendrocyte progenitors, which expressed platelet-derived growth factor receptor-α, did not change in the 2-week-old mouse brain. These results indicate that microglial activation plays an important role in the myelination process, without influencing the number of oligodendrocyte progenitors, in the development of Hexb mice.

FcRγ-dependent immune activation initiates astrogliosis during the asymptomatic phase of Sandhoff disease model mice.

Sandhoff disease (SD) is caused by the loss of ß-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.