The Mutation Matters: CSF Profiles of GCase, Sphingolipids, α-Synuclein in PD(GBA).


Lerche S(1)(2), Schulte C(1)(2), Wurster I(1)(2), Machetanz G(1)(2), Roeben B(1)(2), Zimmermann M(1)(2), Deuschle C(1)(2), Hauser AK(1)(2), Böhringer J(3), Krägeloh-Mann I(3), Waniek K(4), Lachmann I(4), Petterson XT(5), Chiang R(6), Park H(6), Wang B(6), Liepelt-Scarfone I(1)(2), Maetzler W(7), Galasko D(8), Scherzer CR(9), Gasser T(1)(2), Mielke MM(5), Hutten SJ(10), Mollenhauer B(1)(11)(12), Sardi SP(6), Berg D(1)(7), Brockmann K(1)(2).
Author information:
(1)Center of Neurology, Department of Neurodegeneration and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
(2)German Center for Neurodegenerative Diseases, University of Tübingen, Tuebingen, Germany.
(3)Children's Hospital, University of Tübingen, Tübingen, Germany.
(4)Roboscreen GmbH, Leipzig, Germany.
(5)Department of Health Sciences Research and Department of Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
(6)Rare and Neurologic Diseases Therapeutic Area, Sanofi, Cambridge, Massachusetts, USA.
(7)Department of Neurology, Christian-Albrechts University, Kiel, Germany.
(8)Department of Neurology, University of California at San Diego, San Diego, California, USA.
(9)Center for Advanced Parkinson Research, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts, USA.
(10)Michel J. Fox Foundation for Parkinson's Research
(MJFF), New York, New York, USA.
(11)Paracelsus-Elena Klinik Kassel, Kassel, Germany.
(12)Department of Neurology, University Medical Center Goettingen, Göttingen, Germany.


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. © 2021 International Parkinson and Movement Disorder Society.