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Abstract The pathology of Parkinson's Disease (PD) arises from a deposits of oligomeric forms of alpha-synuclein (gene: SNCA, aSyn). Glycosphingolipids facilitate the formation of such oligomers and interfere with their lysosomal degradation. Consequently, mutations in genes involved in glycosphingolipid transport and degradation enhance the risk and severity of PD. In particular, mutations and dysfunctions of acidic glucocerebrosidase (GCase) exacerbate aSyn pathology. Here we studied the accumulation of the GCase substrate, glucosylceramides (GlcCer) in human, mouse and cellular PD and its pathogenic effects. Lipidomic analyses showed elevated GlcCer levels (particularly GlcCer24:1) and a shift of phosphatidylcholines from long to short-C-chain in plasma of PD patients. Primary fibroblasts derived from skin biopsies of PD patients accumulated more GlcCer upon a lysosomal challenge compared to fibroblasts from healthy controls. GlcCer and SHexCer (sulfatides) were markedly increased in the brains of Pink1-/-SNCAA53T double mutant PD mice, and HT22 mouse hippocampal neurons accumulated ceramides and glucosylceramides upon ingestion of pre-formed aSyn fibrils. Conversely, GlcCer24:1 amplified the toxicity of preformed aSyn fibrils. A heterologous G-protein coupled receptor (GPCR) screening did not identify a GPCR as a target of GlcCer24:1, hence excluding a direct interference with dopamine receptors. Instead, RNAseq analysis of GlcCer24:1 treated primary mouse neurons showed an upregulation of genes associated with the "response to glycolipids" resembling responses to pathogens. The data show that extracellular GlcCer is increased in PD reflecting lysosomal dysfunctions, and it elicits an innate immune response in neurons and neighboring cells that may sustain a proinflammatory state.
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