Gaucher disease has recently received wide attention due to the unexpected discovery that it is a genetic risk factor for
Parkinson's disease.
Gaucher disease is caused by the defective activity of the lysosomal
enzyme,
glucocerebrosidase (GCase; GBA1), resulting in intracellular accumulation of the
glycosphingolipids,
glucosylceramide and
psychosine. The rare neuronopathic forms of GD (nGD) are characterized by profound neurological impairment and neuronal cell death. We have previously described the progression of neuropathological changes in a mouse model of nGD. We now examine the relationship between
glycosphingolipid accumulation and initiation of pathology at two pre-symptomatic stages of the disease in four different brain areas which display differential degrees of susceptibility to GCase deficiency. Liquid chromatography electrospray ionization tandem mass spectrometry demonstrated
glucosylceramide and
psychosine accumulation in nGD brains prior to the appearance of
neuroinflammation, although only
glucosylceramide accumulation correlated with
neuroinflammation and neuron loss. Levels of other
sphingolipids, including the pro-apoptotic
lipid,
ceramide, were mostly unaltered. Transmission electron microscopy revealed that
glucosylceramide accumulation occurs in neurons, mostly in the form of membrane-delimited pseudo-tubules located near the nucleus. Highly disrupted
glucosylceramide-storing cells, which are likely degenerating neurons containing massive inclusions, numerous autophagosomes and unique ultrastructural features, were also observed. Together, our results indicate that a certain level of neuronal
glucosylceramide storage is required to trigger neuropathological changes in affected brain areas, while other brain areas containing similar
glucosylceramide levels are unaltered, presumably because of intrinsic differences in neuronal properties, or in the neuronal environment, between various brain regions.