The Mutation Matters: CSF Profiles of GCase, Sphingolipids, α-Synuclein in PDGBA

Stefanie Lerche, Claudia Schulte, Isabel Wurster, Gerrit Machetanz, Benjamin Roeben, Milan Zimmermann, Christian Deuschle, Ann Kathrin Hauser, Judith Böhringer, Ingeborg Krägeloh-Mann, Katharina Waniek, Ingolf Lachmann, Xuan Mai T. Petterson, Ruby Chiang, Hyejung Park, Bing Wang, Inga Liepelt-Scarfone, Walter Maetzler, Douglas Galasko, Clemens R. ScherzerThomas Gasser, Michelle M. Mielke, Samantha J. Hutten, Brit Mollenhauer, S. Pablo Sardi, Daniela Berg, Kathrin Brockmann

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


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

Original languageEnglish (US)
Pages (from-to)1216-1228
Number of pages13
JournalMovement Disorders
Issue number5
StatePublished - May 2021


  • CSF
  • GBA
  • GCase
  • ceramides
  • α-synuclein

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology


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