@article{7e607b5aab1a4806b9135b738c162c9b,
title = "The Mutation Matters: CSF Profiles of GCase, Sphingolipids, α-Synuclein in PDGBA",
abstract = "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.",
keywords = "CSF, GBA, GCase, ceramides, α-synuclein",
author = "Stefanie Lerche and Claudia Schulte and Isabel Wurster and Gerrit Machetanz and Benjamin Roeben and Milan Zimmermann and Christian Deuschle and Hauser, {Ann Kathrin} and Judith B{\"o}hringer and Ingeborg Kr{\"a}geloh-Mann and Katharina Waniek and Ingolf Lachmann and Petterson, {Xuan Mai T.} and Ruby Chiang and Hyejung Park and Bing Wang and Inga Liepelt-Scarfone and Walter Maetzler and Douglas Galasko and Scherzer, {Clemens R.} and Thomas Gasser and Mielke, {Michelle M.} and Hutten, {Samantha J.} and Brit Mollenhauer and Sardi, {S. Pablo} and Daniela Berg and Kathrin Brockmann",
note = "Funding Information: Daniela Berg serves as a consultant for Biogen, BIAL, Lundbeck, UCB Pharma GmbH; serves on speaker's bureaus of AbbVie, Biogen, BIAL, Lundbeck, UCB Pharma GmbH Zambon, Desitin; and receives research support from Michael J. Fox Foundation, Janssen Pharmaceutica N.V., German Parkinson's Disease Association (dPV), BMWi, BMBF, Parkinson Fonds Deutschland gGmbH, UCB Pharma GmbH, TEVA Pharma GmbH, EU, Novartis Pharma GmbH, Lundbeck, and Damp Foundation. Funding Information: Walter Maetzler receives or received funding from the European Union, the German Federal Ministry of Education of Research, Michael J. Fox Foundation, Robert Bosch Foundation, Neuroalliance, Janssen, Lundbeck, Sivantos, and UCB. He received speaker honoraria from AbbVie, Bayer, GlaxoSmithKline, Licher MT, Neuro‐Kolleg Online‐Live, R{\"o}lke Pharma, Takeda, and UCB, was invited to advisory boards of AbbVie, Biogen, Lundbeck, and Market Access & Pricing Strategy GmbH, and is an advisory board member of the Critical Path for Parkinson's Consortium. He serves as the co‐chair of the MDS Technology Task Force. Funding Information: Inga Lieplt‐Scarfone reports the following grants: International Parkinson Funds (Deutschland) GmbH (IPD), Janssen‐Pharmaceutical Companies of Johnson & Johnson, European Commission, H2020‐TWINN‐2015, National Center of Excellence in Research, Luxembourg National Research Fund, and the Michael J. Fox Foundation. Funding Information: Douglas Galasko is supported by NIH grant AGO5131, and by the Michael J. Fox Foundation. He has provided consultation for vTv Pharmaceuticals, Eli Lilly, Inc, and Proclara, Inc. Funding Information: Kathrin Brockmann has received a research grant from the University of Tuebingen (Clinician Scientist) and the German Society of Parkinson's Disease (dpv); funding from the Michael J. Fox Foundation (MJFF) and the German Centre for Neurodegenerative Diseases (DZNE, MIGAP); travel grants from the Movement Disorders Society and speaker honoraria from Abbvie, Lundbeck, UCB, and Zambon. Funding Information: Thomas Gasser serves on the editorial boards of ; holds a patent re: KASPP (LRRK2) Gene, its Production and Use for the Detection and Treatment of Neurodegenerative Diseases; serves as a consultant for Cephalon, Inc. and Merck Serono; serves on speaker's bureaus of Novartis, Merck Serono, SCHWARZ PHARMA, Boehringer Ingelheim, and Valeant Pharmaceuticals International; and receives research support from Novartis, the European Union, BMBF (the Federal Ministry of Education and Research), and Helmholtz Association. Journal of Parkinson's Disease Funding Information: Benjamin Roeben has received financial support for research training at the University of Oxford within the CENTRE‐PD project funded by the European Union's Horizon 2020 research and innovation programme (grant agreement No 692320). Funding Information: Michelle Mielke consults for Brain Protection Company; receives research support from the National Institute on Aging and unrestricted research grants from Biogen. Funding Information: Brit Mollenhauer has received honoraria for consultancy from Roche, Biogen, UCB, and Sun Pharma Advanced Research Company; received research funding from the Deutsche Forschungsgemeinschaft (DFG), EU (Horizon2020), Parkinson Fonds Deutschland, Deutsche Parkinson Vereinigung and the Michael J. Fox Foundation for Parkinson's Research. Funding Information: agencies: This study was funded by the German Center for Neurodegenerative Diseases (DZNE); MIGAP Study. Moreover, it was funded by the PD-Strat project (FKZ 031L0137B), which was supported by the German Federal Ministry of Education and Research (BMBF) in the framework of ERACoSysMed2.Open access funding enabled and organized by Projekt DEAL. Publisher Copyright: {\textcopyright} 2021 International Parkinson and Movement Disorder Society",
year = "2021",
month = may,
doi = "10.1002/mds.28472",
language = "English (US)",
volume = "36",
pages = "1216--1228",
journal = "Movement Disorders",
issn = "0885-3185",
publisher = "John Wiley and Sons Inc.",
number = "5",
}