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PXD026980

PXD026980 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleAltered ceramide metabolism is a feature in the extracellular vesicle mediated spread of alpha-synuclein in sporadic and GBA-linked Lewy body disease
DescriptionMutations in glucocerebrosidase (GBA) are the most prevalent genetic risk factor for Lewy body disorders (LBD) – collectively Parkinson’s disease, Parkinson’s disease dementia and dementia with Lewy bodies. Despite this genetic association, it remains unclear how GBA mutation contributes to the susceptibility of developing LBD. We investigated relationships between LBD-specific glucocerebrosidase deficits, GBA-related pathways, and α-synuclein levels in post-mortem brain tissue from LBD and controls with and without GBA mutations. Our study shows that LBD brains, regardless of GBA mutations, are characterised by altered sphingolipid metabolism, with prominent changes in ceramide species. Since extracellular vesicles (EV) could be involved in LBD pathogenesis by spreading disease linked lipids and proteins, we investigated EV derived from post-mortem cerebrospinal fluid (CSF) and brain tissue from GBA mutation carriers and non-carriers. EV purified from LBD post-mortem CSF and frontal cortex are heavily loaded with ceramides and neurodegeneration-linked proteins including alpha-synuclein and amyloid precursor protein. Our in vitro studies demonstrate that LBD EV constitute a “pathological package” capable of inducing aggregation of wild type alpha-synuclein, potentially through a combination of alpha-synuclein-ceramide interaction and the presence of pathological forms of alpha-synuclein. Together our findings indicate that abnormalities in ceramide metabolism are a feature of LBD, constituting a promising source of biomarkers. GBA mutation likely accelerates the pathological process occurring in sporadic LBD, probably through endolysosomal deficiency, but does not induce alpha-synucleinopathy since healthy normal GBA mutation carriers without alpha-synuclein pathology occur.
HostingRepositoryPRIDE
AnnounceDate2021-11-02
AnnouncementXMLSubmission_2021-11-02_03:39:07.634.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterIvo Fabrik
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList2-pyrrolidone-5-carboxylic acid (Glu); 2-pyrrolidone-5-carboxylic acid (Gln); monohydroxylated residue; acetylated residue; iodoacetamide derivatized residue; deamidated residue
InstrumentQ Exactive HF
Dataset History
RevisionDatetimeStatusChangeLog Entry
02021-06-28 21:22:55ID requested
12021-11-02 03:39:08announced
Publication List
Kurzawa-Akanbi M, Tammireddy S, Fabrik I, Gliaudelyt, ė L, Doherty MK, Heap R, Mate, č, ko-Burmann I, Burmann BM, Trost M, Lucocq JM, Gherman AV, Fairfoul G, Singh P, Burt, é F, Green A, McKeith IG, H, ä, rtlova A, Whitfield PD, Morris CM, Altered ceramide metabolism is a feature in the extracellular vesicle-mediated spread of alpha-synuclein in Lewy body disorders. Acta Neuropathol, 142(6):961-984(2021) [pubmed]
Keyword List
submitter keyword: Lewy body disease, glucocerebrosidase, extracellular vesicles, exosomes, alpha-synuclein, ceramide, inflammation
Contact List
Matthias Trost
contact affiliationNewcastle University Biosciences Institute, Newcastle University, Newcastle upon Tyne, NE24HH, United Kingdom
contact emailmatthias.trost@ncl.ac.uk
lab head
Ivo Fabrik
contact affiliationWallenberg Centre for Molecular and Translational Medicine, University of Gothenburg
contact emailivo.fabrik@gmail.com
dataset submitter
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