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@ARTICLE{Lerche:157806,
      author       = {Lerche, Stefanie and Schulte, Claudia and Wurster, Isabel
                      and Machetanz, Gerrit and Roeben, Benjamin and Zimmermann,
                      Milan and Deuschle, Christian and Hauser, Ann-Kathrin and
                      Böhringer, Judith and Kragelöh-Mann, Ingeborg and Waniek,
                      Katharina and Lachmann, Ingolf and Petterson, Xuan-Mai T and
                      Chiang, Ruby and Park, Hyejung and Wang, Bing and
                      Liepelt-Scarfone, Inga and Maetzler, Walter and Galasko,
                      Douglas and Scherzer, Clemens R and Gasser, Thomas and
                      Mielke, Michelle M and Hutten, Samantha J and Mollenhauer,
                      Brit and Sardi, S Pablo and Berg, Daniela and Brockmann,
                      Kathrin},
      title        = {{T}he {M}utation {M}atters: {CSF} {P}rofiles of {GC}ase,
                      {S}phingolipids, α-{S}ynuclein in {PDGBA}.},
      journal      = {Movement disorders},
      volume       = {36},
      number       = {5},
      issn         = {1531-8257},
      address      = {New York, NY},
      publisher    = {Wiley},
      reportid     = {DZNE-2021-01263},
      pages        = {1216 - 1228},
      year         = {2021},
      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.},
      keywords     = {Glucosylceramidase: genetics / Humans / Mutation: genetics
                      / Parkinson Disease: genetics / Sphingolipids /
                      alpha-Synuclein: genetics / CSF (Other) / GBA (Other) /
                      GCase (Other) / ceramides (Other) / α-synuclein (Other) /
                      Sphingolipids (NLM Chemicals) / alpha-Synuclein (NLM
                      Chemicals) / Glucosylceramidase (NLM Chemicals)},
      cin          = {AG Gasser / AG Berg ; AG Berg / Biobanking Facility
                      Tübingen / Core ICRU / AG Fischer},
      ddc          = {610},
      cid          = {I:(DE-2719)1210000 / I:(DE-2719)5000055 /
                      I:(DE-2719)1240004 / I:(DE-2719)1240005 /
                      I:(DE-2719)1410002},
      pnm          = {353 - Clinical and Health Care Research (POF4-353) / 352 -
                      Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-353 / G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:33547828},
      doi          = {10.1002/mds.28472},
      url          = {https://pub.dzne.de/record/157806},
}