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Sphingolipid changes in Parkinson L444P GBA mutation fibroblasts promote α-synuclein aggregation

View ORCID ProfileCéline Galvagnion, Silvia Cerri, Anthony H.V. Schapira, Fabio Blandini, Donato A. Di Monte
doi: https://doi.org/10.1101/2020.11.09.375048
Céline Galvagnion
1German Center for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1, Building 99, 53127 Bonn, Germany
2Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen Ø, Denmark
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  • ORCID record for Céline Galvagnion
  • For correspondence: celine.galvagnion@sund.ku.dk donato.dimonte@dzne.de
Silvia Cerri
3Laboratory of Cellular and Molecular Neurobiology, IRCCS Mondino Foundation, Pavia, Italy
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Anthony H.V. Schapira
4Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK
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Fabio Blandini
3Laboratory of Cellular and Molecular Neurobiology, IRCCS Mondino Foundation, Pavia, Italy
5Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy
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Donato A. Di Monte
1German Center for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1, Building 99, 53127 Bonn, Germany
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  • For correspondence: celine.galvagnion@sund.ku.dk donato.dimonte@dzne.de
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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 (iPD) and Parkinson 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 iPD cells. It was characterized by an overall increase in sphingolipid levels. It also featured a significant change in the proportion of ceramide, sphingomyelin and hexosylceramide molecules with shorter and longer hydrocarbon chain length; levels of shorter-chain molecules were increased while the percent of longer-chain sphingolipids was decreased in PD-GBA lipid extracts. The extent of this shift was correlated to the degree of reduction of fibroblast glucocerebrosidase activity. In a second set of experiments, lipid extracts from control and PD-GBA fibroblasts were added to incubations of recombinant α-synuclein. The kinetics of α-synuclein aggregation, as assessed by the binding of thioflavin T to amyloid structures, was 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 of shorter-chain sphingolipids. Taken together, 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, which includes an increased content of shorter-chain sphingolipids, could also be an indicator of increased risk for α-synuclein aggregate pathology. Shorter-chain molecules may act as preferred reactants during lipid-induced α-synuclein fibrillation.

Competing Interest Statement

The authors have declared no competing interest.

  • ABBREVIATIONS

    αS
    α-synuclein
    CE
    cholesterol ester
    Cer
    ceramide
    CerS
    ceramide synthase
    Chol
    cholesterol
    CL
    cardiolipin
    DAG
    diacylglycerol
    GBA
    glucocerebrosidase 1 gene
    GCase
    glucocerebrosidase
    GluCer
    Glucosylceramide
    GluSph
    glucosylsphingosine
    HexCer
    hexosylceramide
    iPSC
    induced pluripotent stem cells
    LPA
    lyso-phosphatidate
    LPC
    lyso-phosphatidylcholine
    LPE
    lyso-phosphatidylethanolamine
    LPG
    lyso-phosphatidylglycerol
    LPI
    lyso-phosphatidylinositol
    LPS
    lyso-phosphatidylserine
    PA
    phosphatidate
    PC
    phosphatidylcholine
    PE
    phosphatidylethanolamine
    PG
    phosphatidylglycerol
    PI
    phosphatidylinositol
    PS
    phosphatidylserine
    SL
    sphingolipid
    SM
    sphingomyelin
    TAG
    triacylglycerol
    ThT
    thioflavin T
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    Sphingolipid changes in Parkinson L444P GBA mutation fibroblasts promote α-synuclein aggregation
    Céline Galvagnion, Silvia Cerri, Anthony H.V. Schapira, Fabio Blandini, Donato A. Di Monte
    bioRxiv 2020.11.09.375048; doi: https://doi.org/10.1101/2020.11.09.375048
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    Sphingolipid changes in Parkinson L444P GBA mutation fibroblasts promote α-synuclein aggregation
    Céline Galvagnion, Silvia Cerri, Anthony H.V. Schapira, Fabio Blandini, Donato A. Di Monte
    bioRxiv 2020.11.09.375048; doi: https://doi.org/10.1101/2020.11.09.375048

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