Gaucher disease is caused by a deficiency of glucocerebrosidase. Patients with Gaucher disease are divided into three major phenotypes: chronic nonneuronopathic, acute neuronopathic, and chronic neuronopathic, based on symptoms of the nervous system, the severity of symptoms, and the age of disease onset. The characteristics of patients with acute neuronopathic- and chronic neuronopathic-type Gaucher disease include oculomotor abnormalities, bulbar signs, limb rigidity, seizures and occasional choreoathetoid movements, and neuronal loss. However, the mechanisms leading to the neurodegeneration of this disorder remain unknown. To investigate brain dysfunction in Gaucher disease, we studied the possible role of inflammation in neurodegeneration during development of Gaucher disease in a mouse model. Elevated levels of the proinflammatory cytokines, IL-1alpha, IL-1beta, IL-6, and TNF-alpha, were detected in the fetal brains of Gaucher mice. Moreover, the levels of secreted nitric oxide and reactive oxygen species in the brains of Gaucher mice were higher than in wild-type mice. Thus, accumulated glucocerebroside or glucosylsphingosine, caused by glucocerebrosidase deficiency, may mediate brain inflammation in the Gaucher mouse via the elevation of proinflammatory cytokines, nitric oxide, and reactive oxygen species.
Up-Regulation/genetics ; Tumor Necrosis Factor-alpha/genetics/secretion ; Reverse Transcriptase Polymerase Chain Reaction ; Reactive Oxygen Species/metabolism ; RNA, Messenger/genetics/metabolism ; Nitric Oxide/metabolism ; Microglia/cytology/metabolism ; Mice, Knockout ; Mice, Inbred ICR ; Mice, Inbred C57BL ; Mice ; Interleukin-6/genetics/secretion ; Interleukin-1/genetics/secretion ; Inflammation/immunology ; Glucosylceramidase/genetics ; Gaucher Disease/*genetics/metabolism/pathology ; Cytokines/*genetics/immunology/secretion ; Cells, Cultured ; Brain/embryology/*metabolism/pathology ; Animals