PXD026980 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | Altered ceramide metabolism is a feature in the extracellular vesicle mediated spread of alpha-synuclein in sporadic and GBA-linked Lewy body disease |
Description | Mutations 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. |
HostingRepository | PRIDE |
AnnounceDate | 2021-11-02 |
AnnouncementXML | Submission_2021-11-02_03:39:07.634.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Ivo Fabrik |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | 2-pyrrolidone-5-carboxylic acid (Glu); 2-pyrrolidone-5-carboxylic acid (Gln); monohydroxylated residue; acetylated residue; iodoacetamide derivatized residue; deamidated residue |
Instrument | Q Exactive HF |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2021-06-28 21:22:55 | ID requested | |
⏵ 1 | 2021-11-02 03:39:08 | announced | |
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 affiliation | Newcastle University Biosciences Institute, Newcastle University, Newcastle upon Tyne, NE24HH, United Kingdom |
contact email | matthias.trost@ncl.ac.uk |
lab head | |
Ivo Fabrik |
contact affiliation | Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg |
contact email | ivo.fabrik@gmail.com |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
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- PRIDE
- PXD026980
- Label: PRIDE project
- Name: Altered ceramide metabolism is a feature in the extracellular vesicle mediated spread of alpha-synuclein in sporadic and GBA-linked Lewy body disease