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.
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 PDGBApatients 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.
Authors: Phillip D Whitfield; Christopher M Morris; Marzena Kurzawa-Akanbi; Seshu Tammireddy; Ivo Fabrik; Lina Gliaudelytė; Mary K Doherty; Rachel Heap; Irena Matečko-Burmann; Björn M Burmann; Matthias Trost; John M Lucocq; Anda V Gherman; Graham Fairfoul; Preeti Singh; Florence Burté; Alison Green; Ian G McKeith; Anetta Härtlova Journal: Acta Neuropathol Date: 2021-09-13 Impact factor: 17.088
Authors: Catherine Viel; Jennifer Clarke; Can Kayatekin; Amy M Richards; Ming Sum R Chiang; Hyejung Park; Bing Wang; Lamya S Shihabuddin; S Pablo Sardi Journal: Sci Rep Date: 2021-10-22 Impact factor: 4.379
Authors: Kerri-Lee Wallom; María E Fernández-Suárez; David A Priestman; Danielle Te Vruchte; Mylene Huebecker; Penelope J Hallett; Ole Isacson; Frances M Platt Journal: Glycoconj J Date: 2021-11-10 Impact factor: 2.916
Authors: M Judith Peterschmitt; Hidemoto Saiki; Taku Hatano; Thomas Gasser; Stuart H Isaacson; Sebastiaan J M Gaemers; Pascal Minini; Stéphane Saubadu; Jyoti Sharma; Samantha Walbillic; Roy N Alcalay; Gary Cutter; Nobutaka Hattori; Günter U Höglinger; Kenneth Marek; Anthony H V Schapira; Clemens R Scherzer; Tanya Simuni; Nir Giladi; Sergio Pablo Sardi; Tanya Z Fischer Journal: J Parkinsons Dis Date: 2022 Impact factor: 5.568
Authors: Nathan Hwangbo; Xinyu Zhang; Daniel Raftery; Haiwei Gu; Shu-Ching Hu; Thomas J Montine; Joseph F Quinn; Kathryn A Chung; Amie L Hiller; Dongfang Wang; Qiang Fei; Lisa Bettcher; Cyrus P Zabetian; Elaine R Peskind; Ge Li; Daniel E L Promislow; Marie Y Davis; Alexander Franks Journal: Metabolites Date: 2022-03-22