Spatial and temporal correlation between neuron loss and neuroinflammation in a mouse model of neuronopathic Gaucher disease.

Gaucher disease (GD), the most common lysosomal storage disorder, is caused by a deficiency in the lysosomal enzyme glucocerebrosidase (GlcCerase), which results in intracellular accumulation of glucosylceramide (GlcCer). The rare neuronopathic forms of GD are characterized by profound neurological impairment and neuronal cell death, but little is known about the neuropathological changes that underlie these events. We now systematically examine the onset and progression of various neuropathological changes (including microglial activation, astrogliosis and neuron loss) in a mouse model of neuronopathic GD, and document the brain areas that are first affected, which may reflect vulnerability of these areas to GlcCerase deficiency. We also identify neuropathological changes in several brain areas and pathways, such as the substantia nigra reticulata, reticulotegmental nucleus of the pons, cochlear nucleus and the somatosensory system, which could be responsible for some of the neurological manifestations of the human disease. In addition, we establish that microglial activation and astrogliosis are spatially and temporally correlated with selective neuron loss.