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000164070 041__ $$aEnglish
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000164070 1001_ $$0P:(DE-2719)2811987$$aGalvagnion, Céline$$b0$$eFirst author$$udzne
000164070 245__ $$aSphingolipid changes in Parkinson L444P GBA mutation fibroblasts promote α-synuclein aggregation.
000164070 260__ $$aOxford$$bOxford Univ. Press$$c2022
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000164070 520__ $$aIntraneuronal 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.
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000164070 650_7 $$2Other$$a           GBA         
000164070 650_7 $$2Other$$aParkinson’s disease
000164070 650_7 $$2Other$$afibroblasts
000164070 650_7 $$2Other$$alipidomics
000164070 650_7 $$2Other$$aα-synuclein
000164070 650_7 $$2NLM Chemicals$$aSNCA protein, human
000164070 650_7 $$2NLM Chemicals$$aSphingolipids
000164070 650_7 $$2NLM Chemicals$$aalpha-Synuclein
000164070 650_7 $$0EC 3.2.1.45$$2NLM Chemicals$$aGBA protein, human
000164070 650_7 $$0EC 3.2.1.45$$2NLM Chemicals$$aGlucosylceramidase
000164070 650_2 $$2MeSH$$aFibroblasts: metabolism
000164070 650_2 $$2MeSH$$aGlucosylceramidase: genetics
000164070 650_2 $$2MeSH$$aGlucosylceramidase: metabolism
000164070 650_2 $$2MeSH$$aHumans
000164070 650_2 $$2MeSH$$aMutation: genetics
000164070 650_2 $$2MeSH$$aParkinson Disease: metabolism
000164070 650_2 $$2MeSH$$aSphingolipids
000164070 650_2 $$2MeSH$$aalpha-Synuclein: genetics
000164070 650_2 $$2MeSH$$aalpha-Synuclein: metabolism
000164070 7001_ $$aMarlet, Frederik Ravnkilde$$b1
000164070 7001_ $$aCerri, Silvia$$b2
000164070 7001_ $$00000-0002-3018-3966$$aSchapira, Anthony H V$$b3
000164070 7001_ $$aBlandini, Fabio$$b4
000164070 7001_ $$0P:(DE-2719)2481741$$aDi Monte, Donato A$$b5$$eLast author$$udzne
000164070 773__ $$0PERI:(DE-600)1474117-9$$a10.1093/brain/awab371$$gVol. 145, no. 3, p. 1038 - 1051$$n3$$p1038 - 1051$$tBrain$$v145$$x0006-8950$$y2022
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