[Pathophysiology of Sandhoff Disease and Novel Thrapeutic Targets]

Sandhoff disease (SD) is a glycosphingolipid storage disease resulting from a genetic mutation in HEXB and associated deficiency in β-hexosaminidase activity. This defect causes abnormal accumulation of ganglioside GM2 and related glycolipids in lysosomes, resulting in progressive deterioration of the central nervous system. Hexb-knockout (Hexb^-/-) mice, an established animal model, show abnormalities similar to the severe phenotype seen in human infants. We used iPS cells derived from this mouse model (SD-iPSCs) to examine abnormal neuronal lineage differentiation and development in vitro during the asymptomatic phase of SD. Differentiation ability along the time axis appears to be altered in SD-iPSCs in which the differentiation ability of neural stem cells is promoted and differentiation into neurons is completed earlier, while the timing of differentiation into astrocytes is accelerated. This abnormal differentiation was suppressed by introducing the Hexb gene. These results indicate that the abnormal differentiation of SD-iPSCs into the nervous system reflects the pathogenesis of SD. Analysis using Hexb^-/- mice revealed that activated microglia causes astrogliosis at the early stage of development that can be ameliorated via immunosuppression. Furthermore, reactive astrocytes in the cortex of Hexb^-/- mice express adenosine A_2A receptors in the late inflammatory phase. Inhibition of this receptor resulted in a decrease in activated microglial cells and inflammatory cytokines/chemokines. These results suggest that the astrocyte A_2A receptor is important as a sensor that regulates microglial activation in the late inflammatory phase. Thus, our results provide new insights into the complex pathogenesis of SD.