Journal Article

DZNE-2021-01263

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The Mutation Matters: CSF Profiles of GCase, Sphingolipids, α-Synuclein in PDGBA.

Lerche, S. (First author)DZNE* ; Schulte, C.DZNE* ; Wurster, I.DZNE* ; Machetanz, G.DZNE* ; Roeben, B.DZNE* ; Zimmermann, M.DZNE* ; Deuschle, C.DZNE* ; Hauser, A.-K.DZNE* ; Böhringer, J. ; Kragelöh-Mann, I.Extern* ; Waniek, K. ; Lachmann, I. ; Petterson, X. T. ; Chiang, R. ; Park, H. ; Wang, B. ; Liepelt-Scarfone, I.DZNE* ; Maetzler, W.Extern* ; Galasko, D. ; Scherzer, C. R. ; Gasser, T.DZNE* ; Mielke, M. M. ; Hutten, S. J. ; Mollenhauer, B.Extern* ; Sardi, S. P. ; Berg, D.Extern* ; Brockmann, K. (Last author)DZNE*

2021
Wiley New York, NY

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Please use a persistent id in citations: doi:10.1002/mds.28472

Abstract: 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.To explore GBA-pathway-specific biomarker profiles cross-sectionally (TUEPAC-MIGAP, PPMI) and longitudinally (PPMI).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.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 .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.

Keyword(s): Glucosylceramidase: genetics (MeSH) ; Humans (MeSH) ; Mutation: genetics (MeSH) ; Parkinson Disease: genetics (MeSH) ; Sphingolipids (MeSH) ; alpha-Synuclein: genetics (MeSH) ; CSF ; GBA ; GCase ; ceramides ; α-synuclein ; Sphingolipids ; alpha-Synuclein ; Glucosylceramidase

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Contributing Institute(s):

1. Parkinson Genetics (AG Gasser)
2. Parkinson's Disease Genetics (AG Berg ; AG Berg)
3. Biobanking Facility Tübingen (Biobanking Facility Tübingen)
4. Core ICRU (Core ICRU)
5. Epigenetics and Systems Medicine in Neurodegenerative Diseases (AG Fischer)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)
2. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2021

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Database coverage:
; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; DEAL Wiley ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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