Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 May;36(5):1216-1228.
doi: 10.1002/mds.28472. Epub 2021 Feb 6.

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

Stefanie Lerche  1   2 , Claudia Schulte  1   2 , Isabel Wurster  1   2 , Gerrit Machetanz  1   2 , Benjamin Roeben  1   2 , Milan Zimmermann  1   2 , Christian Deuschle  1   2 , Ann-Kathrin Hauser  1   2 , Judith Böhringer  3 , Ingeborg Krägeloh-Mann  3 , Katharina Waniek  4 , Ingolf Lachmann  4 , Xuan-Mai T Petterson  5 , Ruby Chiang  6 , Hyejung Park  6 , Bing Wang  6 , Inga Liepelt-Scarfone  1   2 , Walter Maetzler  7 , Douglas Galasko  8 , Clemens R Scherzer  9 , Thomas Gasser  1   2 , Michelle M Mielke  5 , Samantha J Hutten  10 , Brit Mollenhauer  1   11   12 , S Pablo Sardi  6 , Daniela Berg  1   7 , Kathrin Brockmann  1   2
Affiliations

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

Stefanie Lerche et al. Mov Disord. 2021 May.

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. © 2021 International Parkinson and Movement Disorder Society.

Keywords: CSF; GBA; GCase; ceramides; α-synuclein.

PubMed Disclaimer

References

    1. Sidransky E, Nalls MA, Aasly JO, et al. Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. N Engl J Med 2009;361(17):1651-1661.
    1. Brockmann K, Srulijes K, Hauser AK, et al. GBA-associated PD presents with nonmotor characteristics. Neurology 2011;77(3):276-280.
    1. Brockmann K, Srulijes K, Pflederer S, et al. GBA-associated Parkinson's disease: reduced survival and more rapid progression in a prospective longitudinal study. Mov Disord 2015;30(3):407-411.
    1. Cilia R, Tunesi S, Marotta G, et al. Survival and dementia in GBA-associated Parkinson's disease: the mutation matters. Ann Neurol 2016;80(5):662-673.
    1. Liu G, Boot B, Locascio JJ, et al. Specifically neuropathic Gaucher's mutations accelerate cognitive decline in Parkinson's. Ann Neurol 2016;80(5):674-685.

Publication types

LinkOut - more resources