Gaucher disease is a glycosphingolipid storage disease caused by deficiency of glucocerebrosidase, resulting in the accumulation of glucosylceramide in lysosomes. The neuronopathic forms of this disease are associated with neuronal loss and neurodegeneration. However, the pathophysiological mechanisms leading to prenatal and neonatal death remain uncharacterized. To investigate brain dysfunction in Gaucher disease, we studied the effects of neurotrophic factors during development in a mouse model of Gaucher disease. The expression of brain-derived neurotrophic factor and nerve growth factor was reduced in the cerebral cortex, brainstem, and cerebellum of Gaucher mice, compared with that in wild-type mice. Extracellular signal-regulated kinase (ERK) 1/2 expression was downregulated in neurons from Gaucher mice and correlated with a decreased number of neurons. These results suggest that a reduction in neurotrophic factors could be involved in neuronal loss in Gaucher disease.
Signal Transduction ; Neurons/*metabolism ; Nerve Growth Factors/*metabolism ; Models, Animal ; Mice, Inbred C57BL ; Mice ; MAP Kinase Signaling System/physiology ; Gaucher Disease/*metabolism/pathology ; Down-Regulation ; Cells, Cultured ; Cell Survival ; Brain/*metabolism ; Animals

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