164070 20240319115432.0 10.1093/brain/awab371 doi pmid:35362022 pmid pmc:PMC9050548 pmc 0006-8950 ISSN 1460-2156 ISSN altmetric:125741640 altmetric DZNE-2022-00733 English 610 Galvagnion, Céline P:(DE-2719)2811987 0 First author dzne Sphingolipid changes in Parkinson L444P GBA mutation fibroblasts promote α-synuclein aggregation. Oxford 2022 Oxford Univ. Press article DRIVER Output Types/Journal article DataCite Journal Article journal journal PUB:(DE-HGF)16 1655210388_926 PUB:(DE-HGF) ARTICLE BibTeX JOURNAL_ARTICLE ORCID Journal Article 0 EndNote (CC BY-NC) 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. 352 - Disease Mechanisms (POF4-352) G:(DE-HGF)POF4-352 POF4-352 POF IV 0 Dataset connected to CrossRef, PubMed, , Journals: pub.dzne.de 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 EC 3.2.1.45 NLM Chemicals Glucosylceramidase EC 3.2.1.45 NLM Chemicals Fibroblasts: metabolism MeSH Glucosylceramidase: genetics MeSH Glucosylceramidase: metabolism MeSH Humans MeSH Mutation: genetics MeSH Parkinson Disease: metabolism MeSH Sphingolipids MeSH alpha-Synuclein: genetics MeSH alpha-Synuclein: metabolism MeSH Marlet, Frederik Ravnkilde 1 Cerri, Silvia 2 Schapira, Anthony H V 0000-0002-3018-3966 3 Blandini, Fabio 4 Di Monte, Donato A P:(DE-2719)2481741 5 Last author dzne 10.1093/brain/awab371 Vol. 145, no. 3, p. 1038 - 1051 PERI:(DE-600)1474117-9 3 1038 - 1051 Brain 145 2022 0006-8950 OpenAccess http://pub.dzne.de/record/164070/files/DZNE-2022-00733.pdf OpenAccess pdfa http://pub.dzne.de/record/164070/files/DZNE-2022-00733.pdf?subformat=pdfa oai:pub.dzne.de:164070 openaire open_access VDB driver dnbdelivery Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 0 P:(DE-2719)2811987 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 5 P:(DE-2719)2481741 DE-HGF Gesundheit Neurodegenerative Diseases G:(DE-HGF)POF4-350 G:(DE-HGF)POF4-352 G:(DE-HGF)POF4 G:(DE-HGF)POF4-300 G:(DE-HGF)POF Disease Mechanisms 0 2022 DBCoverage StatID:(DE-HGF)0200 StatID SCOPUS 2022-11-09 DBCoverage StatID:(DE-HGF)0300 StatID Medline 2022-11-09 DBCoverage StatID:(DE-HGF)1050 StatID BIOSIS Previews 2022-11-09 DBCoverage StatID:(DE-HGF)1190 StatID Biological Abstracts 2021-01-29 DBCoverage StatID:(DE-HGF)0600 StatID Ebsco Academic Search 2022-11-09 IF >= 15 StatID:(DE-HGF)9915 StatID BRAIN : 2021 2022-11-09 JCR StatID:(DE-HGF)0100 StatID BRAIN : 2021 2022-11-09 Creative Commons Attribution-NonCommercial CC BY-NC 4.0 LIC:(DE-HGF)CCBYNC4 HGFVOC WoS StatID:(DE-HGF)0113 StatID Science Citation Index Expanded 2021-01-29 DBCoverage StatID:(DE-HGF)1030 StatID Current Contents - Life Sciences 2022-11-09 OpenAccess StatID:(DE-HGF)0510 StatID DBCoverage StatID:(DE-HGF)0150 StatID Web of Science Core Collection 2022-11-09 Peer Review StatID:(DE-HGF)0030 StatID ASC 2022-11-09 DBCoverage StatID:(DE-HGF)0160 StatID Essential Science Indicators 2021-01-29 DBCoverage StatID:(DE-HGF)1110 StatID Current Contents - Clinical Medicine 2022-11-09 Nationallizenz StatID:(DE-HGF)0420 StatID 2022-11-09 ger DBCoverage StatID:(DE-HGF)0199 StatID Clarivate Analytics Master Journal List 2022-11-09 I:(DE-2719)1013008 AG Di Monte Neurodegeneration and Neuroprotection in Parkinson´s Disease 0 journal VDB UNRESTRICTED I:(DE-2719)1013008 FullTexts