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@ARTICLE{Galvagnion:164070,
      author       = {Galvagnion, Céline and Marlet, Frederik Ravnkilde and
                      Cerri, Silvia and Schapira, Anthony H V and Blandini, Fabio
                      and Di Monte, Donato A},
      title        = {{S}phingolipid changes in {P}arkinson {L}444{P} {GBA}
                      mutation fibroblasts promote α-synuclein aggregation.},
      journal      = {Brain},
      volume       = {145},
      number       = {3},
      issn         = {0006-8950},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {DZNE-2022-00733},
      pages        = {1038 - 1051},
      year         = {2022},
      note         = {(CC BY-NC)},
      abstract     = {Intraneuronal accumulation of aggregated α-synuclein is a
                      pathological hallmark of Parkinson's disease. Therefore,
                      mechanisms capable of promoting α-synuclein deposition bear
                      important pathogenetic implications. Mutations of the
                      glucocerebrosidase 1 (GBA) gene represent a prevalent
                      Parkinson's disease risk factor. They are associated with
                      loss of activity of a key enzyme involved in lipid
                      metabolism, glucocerebrosidase, supporting a mechanistic
                      relationship between abnormal α-synuclein-lipid
                      interactions and the development of Parkinson pathology. In
                      this study, the lipid membrane composition of fibroblasts
                      isolated from control subjects, patients with idiopathic
                      Parkinson's disease and Parkinson's disease patients
                      carrying the L444P GBA mutation (PD-GBA) was assayed using
                      shotgun lipidomics. The lipid profile of PD-GBA fibroblasts
                      differed significantly from that of control and idiopathic
                      Parkinson's disease cells. It was characterized by an
                      overall increase in sphingolipid levels. It also featured a
                      significant increase in the proportion of ceramide,
                      sphingomyelin and hexosylceramide molecules with shorter
                      chain length and a decrease in the percentage of
                      longer-chain sphingolipids. The extent of this shift was
                      correlated to the degree of reduction of fibroblast
                      glucocerebrosidase activity. Lipid extracts from control and
                      PD-GBA fibroblasts were added to recombinant α-synuclein
                      solutions. The kinetics of α-synuclein aggregation were
                      significantly accelerated after addition of PD-GBA extracts
                      as compared to control samples. Amyloid fibrils collected at
                      the end of these incubations contained lipids, indicating
                      α-synuclein-lipid co-assembly. Lipids extracted from
                      α-synuclein fibrils were also analysed by shotgun
                      lipidomics. Data revealed that the lipid content of these
                      fibrils was significantly enriched by shorter-chain
                      sphingolipids. In a final set of experiments, control and
                      PD-GBA fibroblasts were incubated in the presence of the
                      small molecule chaperone ambroxol. This treatment restored
                      glucocerebrosidase activity and sphingolipid levels and
                      composition of PD-GBA cells. It also reversed the
                      pro-aggregation effect that lipid extracts from PD-GBA
                      fibroblasts had on α-synuclein. Taken together, the
                      findings of this study indicate that the L444P GBA mutation
                      and consequent enzymatic loss are associated with a
                      distinctly altered membrane lipid profile that provides a
                      biological fingerprint of this mutation in Parkinson
                      fibroblasts. This altered lipid profile could also be an
                      indicator of increased risk for α-synuclein aggregate
                      pathology.},
      keywords     = {Fibroblasts: metabolism / Glucosylceramidase: genetics /
                      Glucosylceramidase: metabolism / Humans / Mutation: genetics
                      / Parkinson Disease: metabolism / Sphingolipids /
                      alpha-Synuclein: genetics / alpha-Synuclein: metabolism /
                      GBA (Other) / Parkinson’s disease (Other) / fibroblasts
                      (Other) / lipidomics (Other) / α-synuclein (Other) / SNCA
                      protein, human (NLM Chemicals) / Sphingolipids (NLM
                      Chemicals) / alpha-Synuclein (NLM Chemicals) / GBA protein,
                      human (NLM Chemicals) / Glucosylceramidase (NLM Chemicals)},
      cin          = {AG Di Monte},
      ddc          = {610},
      cid          = {I:(DE-2719)1013008},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:35362022},
      pmc          = {pmc:PMC9050548},
      doi          = {10.1093/brain/awab371},
      url          = {https://pub.dzne.de/record/164070},
}