The Mutation Matters: <scp>CSF</scp> Profiles of <scp>GCase</scp> , Sphingolipids, ??Synuclein in <scp> PD _GBA </scp>

Background With pathway-specific trials in PD associated with variants the glucocerebrosidase gene (PDGBA) under way, we need markers that confirm impact of genetic patient-derived biofluids order to allow patient stratification merely based on genetics and might serve as biochemical read-out for target engagement. Objective To explore GBA-pathway-specific biomarker profiles cross-sectionally (TUEPAC-MIGAP, PPMI) longitudinally (PPMI). Methods We measured enzyme activity lysosomal glucocerebrosidase, CSF levels glucosylceramides (upstream substrate glucocerebrosidase), ceramides (downstream product lactosylceramides, sphingosines, sphingomyelin (by-products) total ?-synuclein PDGBA patients compared PDGBA_wildtype patients. Results Cross-sectionally both cohorts PPMI: (1) was significantly lower PDGBA_wildtype. (2) upstream substrates (glucosylceramides species) were higher (3) All these findings most pronounced severe mutations (PDGBA_severe). TUEPAC-MIGAP PPMI, downstream-products (ceramides) PDGBA_severe. by-products sphinganine sphingosine-1-phosphate PPMI species lactosylceramides Interpretation These GBA have a relevant functional Bridging gap between now allows clinical mutation status. Importantly, all prominent variants. © 2021 International Parkinson Movement Disorder Society