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

Stefanie Lerche; Claudia Schulte; Isabel Wurster; Gerrit Machetanz; Benjamin Roeben; Milan Zimmermann; Christian Deuschle; Ann Kathrin Hauser; Judith Böhringer; Ingeborg Krägeloh-Mann; Katharina Waniek; Ingolf Lachmann; Xuan Mai T. Petterson; Ruby Chiang; Hyejung Park; Bing Wang; Inga Liepelt-Scarfone; Walter Maetzler; Douglas Galasko; Clemens R. Scherzer; Thomas Gasser; Michelle M. Mielke; Samantha J. Hutten; Brit Mollenhauer; S. Pablo Sardi; Daniela Berg; Kathrin Brockmann

doi:10.1002/mds.28472

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

Stefanie Lerche, Claudia Schulte, Isabel Wurster, Gerrit Machetanz, Benjamin Roeben, Milan Zimmermann, Christian Deuschle, Ann Kathrin Hauser, Judith Böhringer, Ingeborg Krägeloh-Mann, Katharina Waniek, Ingolf Lachmann, Xuan Mai T. Petterson, Ruby Chiang, Hyejung Park, Bing Wang, Inga Liepelt-Scarfone, Walter Maetzler, Douglas Galasko, Clemens R. ScherzerThomas Gasser, Michelle M. Mielke, Samantha J. Hutten, Brit Mollenhauer, S. Pablo Sardi, Daniela Berg, Kathrin Brockmann

Quantitative Health Sciences

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

Background: With pathway-specific trials in PD associated with variants in the glucocerebrosidase gene (PD_GBA) 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 PD_GBA patients compared to PD_{GBA_wildtype} patients. Results: Cross-sectionally in both cohorts and longitudinally in PPMI: (1) glucocerebrosidase activity was significantly lower in PD_GBA compared to PD_{GBA_wildtype}. (2) CSF levels of upstream substrates (glucosylceramides species) were higher in PD_GBA compared to PD_{GBA_wildtype}. (3) CSF levels of total α-synuclein were lower in PD_GBA compared to PD_{GBA_wildtype}. All of these findings were most pronounced in PD_GBA with severe mutations (PD_{GBA_severe}). Cross-sectionally in TUEPAC-MIGAP and longitudinally in PPMI, CSF levels of downstream-products (ceramides) were higher in PD_{GBA_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 PD_{GBA_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 PD_GBA with severe variants.

Original language	English (US)
Pages (from-to)	1216-1228
Number of pages	13
Journal	Movement Disorders
Volume	36
Issue number	5
DOIs	https://doi.org/10.1002/mds.28472
State	Published - May 2021

Keywords

CSF
GBA
GCase
ceramides
α-synuclein

ASJC Scopus subject areas

Neurology
Clinical Neurology

Access to Document

10.1002/mds.28472

Cite this

Lerche, S., Schulte, C., Wurster, I., Machetanz, G., Roeben, B., Zimmermann, M., Deuschle, C., Hauser, A. K., Böhringer, J., Krägeloh-Mann, I., Waniek, K., Lachmann, I., Petterson, X. M. T., Chiang, R., Park, H., Wang, B., Liepelt-Scarfone, I., Maetzler, W., Galasko, D., ... Brockmann, K. (2021). The Mutation Matters: CSF Profiles of GCase, Sphingolipids, α-Synuclein in PD_GBA. Movement Disorders, 36(5), 1216-1228. https://doi.org/10.1002/mds.28472

Lerche, S, Schulte, C, Wurster, I, Machetanz, G, Roeben, B, Zimmermann, M, Deuschle, C, Hauser, AK, Böhringer, J, Krägeloh-Mann, I, Waniek, K, Lachmann, I, Petterson, XMT, Chiang, R, Park, H, Wang, B, Liepelt-Scarfone, I, Maetzler, W, Galasko, D, Scherzer, CR, Gasser, T, Mielke, MM, Hutten, SJ, Mollenhauer, B, Sardi, SP, Berg, D & Brockmann, K 2021, 'The Mutation Matters: CSF Profiles of GCase, Sphingolipids, α-Synuclein in PD_GBA', Movement Disorders, vol. 36, no. 5, pp. 1216-1228. https://doi.org/10.1002/mds.28472

@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 = "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",

}

TY - JOUR

T1 - The Mutation Matters

T2 - CSF Profiles of GCase, Sphingolipids, α-Synuclein in PDGBA

AU - Lerche, Stefanie

AU - Schulte, Claudia

AU - Wurster, Isabel

AU - Machetanz, Gerrit

AU - Roeben, Benjamin

AU - Zimmermann, Milan

AU - Deuschle, Christian

AU - Hauser, Ann Kathrin

AU - Böhringer, Judith

AU - Krägeloh-Mann, Ingeborg

AU - Waniek, Katharina

AU - Lachmann, Ingolf

AU - Petterson, Xuan Mai T.

AU - Chiang, Ruby

AU - Park, Hyejung

AU - Wang, Bing

AU - Liepelt-Scarfone, Inga

AU - Maetzler, Walter

AU - Galasko, Douglas

AU - Scherzer, Clemens R.

AU - Gasser, Thomas

AU - Mielke, Michelle M.

AU - Hutten, Samantha J.

AU - Mollenhauer, Brit

AU - Sardi, S. Pablo

AU - Berg, Daniela

AU - Brockmann, Kathrin

PY - 2021/5

Y1 - 2021/5

N2 - 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.

AB - 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.

KW - CSF

KW - GBA

KW - GCase

KW - ceramides

KW - α-synuclein

UR - http://www.scopus.com/inward/record.url?scp=85100595355&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85100595355&partnerID=8YFLogxK

U2 - 10.1002/mds.28472

DO - 10.1002/mds.28472

M3 - Article

C2 - 33547828

AN - SCOPUS:85100595355

SN - 0885-3185

VL - 36

SP - 1216

EP - 1228

JO - Movement Disorders

JF - Movement Disorders

IS - 5

ER -