PXD026980

PXD026980 is an original dataset announced via ProteomeXchange.

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

Revision	Datetime	Status	ChangeLog Entry
0	2021-06-28 21:22:55	ID requested
⏵ 1	2021-11-02 03:39:08	announced

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]

submitter keyword: Lewy body disease, glucocerebrosidase, extracellular vesicles, exosomes, alpha-synuclein, ceramide, inflammation

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

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PRIDE project URI

• PRIDE
  1. PXD026980
     1. Label: PRIDE project
     2. Name: Altered ceramide metabolism is a feature in the extracellular vesicle mediated spread of alpha-synuclein in sporadic and GBA-linked Lewy body disease