Microglial Activation in Sandhoff Disease and Suppression After Bone Marrow Transplantation. R. Wada¹, F. Norflus¹, C.J. Tifft^1,2, R.L. Proia¹. 1) Genetics of Development and Disease Branch, NIDDK, NIH, Bethesda, MD; 2) Department of Medical Genetics, Children's Natl Medical Center, Washington DC.

   In glycosphingolipid (GSL) storage diseases, such as Tay-Sachs disease, Sandhoff disease and some forms of Gaucher disease, an inherited lysosomal enzyme deficiency results in the accumulation of GSLs in the central nervous system (CNS). The GSL accretion leads to neuronal dysfunction and apoptosis through pathogenic mechanisms that are only poorly understood. We have studied a Sandhoff disease mouse as a prototype for the GSL storage diseases to uncover mechanisms of neurodegeneration. At 4 months old, when neurologic manifestations were extreme, apoptotic neuronal cell death was prominent in thalamic nuclei, brainstem and spinal cord. Global gene expression analysis using cDNA microarrays containing approximately 8,000 sequences revealed an up-regulation of macrophage/microglial genes in the CNS of 4 month old Sandhoff disease mice. Immunohistological analysis confirmed that CNS regions exhibiting prominent apoptotic neuronal death were populated by expanded numbers of macrophages/microglia. These macrophages/microglia intensely expressed markers of activation. In brain samples from a human case of Sandhoff disease, macrophage/microglial expansion and activation was confirmed. Bone marrow transplantation (BMT) of Sandhoff disease mice ameliorated neurologic manifestations and apoptotic neuronal death without demonstrable reduction in CNS storage of GSLs. We have found that BMT suppressed macrophage/microglial expansion and activation. These findings implicate the activation of the macrophage/microglial system in the neurodegeneration of Sandhoff disease and possibly other GSL storage diseases. They also suggest that the therapeutic effect of bone marrow transplantation is, in part, the result of the suppression of macrophage/microglial activation.