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Altered ceramide metabolism is a feature in the extracellular vesicle-mediated spread of alpha-synuclein in Lewy body disorders
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dc.contributor.author | Kurzawa-Akanbi, Marzena | |
dc.contributor.author | Tammireddy, Seshu | |
dc.contributor.author | Fabrik, Ivo | |
dc.contributor.author | Gliaudelytė, Lina | |
dc.contributor.author | Doherty, Mary K. | |
dc.contributor.author | Heap, Rachel | |
dc.contributor.author | Matečko-Burmann, Irena | |
dc.contributor.author | Burmann, Björn M. | |
dc.contributor.author | Trost, Matthias | |
dc.contributor.author | Lucocq, John M. | |
dc.contributor.author | Gherman, Anda V. | |
dc.contributor.author | Fairfoul, Graham | |
dc.contributor.author | Singh, Preeti | |
dc.contributor.author | Burté, Florence | |
dc.contributor.author | Green, Alison | |
dc.contributor.author | McKeith, Ian G. | |
dc.contributor.author | Härtlova, Anetta | |
dc.contributor.author | Whitfield, Phillip D. | |
dc.contributor.author | Morris, Christopher M. | |
dc.date.accessioned | 2021-09-23T15:30:11Z | |
dc.date.available | 2021-09-23T15:30:11Z | |
dc.date.issued | 2021-09-13 | |
dc.identifier.citation | Kurzawa-Akanbi , M , Tammireddy , S , Fabrik , I , Gliaudelytė , L , Doherty , M K , Heap , R , Matečko-Burmann , I , Burmann , B M , Trost , M , Lucocq , J M , Gherman , A V , Fairfoul , G , Singh , P , Burté , F , Green , A , McKeith , I G , Härtlova , A , Whitfield , P D & Morris , C M 2021 , ' Altered ceramide metabolism is a feature in the extracellular vesicle-mediated spread of alpha-synuclein in Lewy body disorders ' , Acta Neuropathologica . https://doi.org/10.1007/s00401-021-02367-3 | en |
dc.identifier.issn | 1432-0533 | |
dc.identifier.other | PURE: 275855882 | |
dc.identifier.other | PURE UUID: cafa2f52-ae23-4da7-a591-cd24f7ed4339 | |
dc.identifier.other | RIS: urn:7327579A8C0A6120EC761E0A4A85DA41 | |
dc.identifier.other | RIS: Kurzawa-Akanbi2021 | |
dc.identifier.other | ORCID: /0000-0002-5191-0093/work/100172602 | |
dc.identifier.other | WOS: 000695119600001 | |
dc.identifier.other | Scopus: 85114782456 | |
dc.identifier.uri | https://hdl.handle.net/10023/24013 | |
dc.description | This study was funded by the Lewy Body Society and the Michael J. Fox Foundation for Parkinson’s Research. A.H. and B.M.B. gratefully acknowledge funding from the Knut och Alice Wallenberg Stiftelse through the Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Sweden. S.T., M.K.D. and P.D.W. gratefully acknowledge the financial support of the European Regional Development Fund, Scottish Funding Council and Highlands and Islands Enterprise. Newcastle University TEM Services acknowledge BBSRC support (Grant code BB/R013942/1). The Research was supported by the National Institute for Health Research Newcastle Biomedical Research Centre based at Newcastle Hospitals NHS Foundation Trust and Newcastle University. The Newcastle Brain Tissue Resource is supported by grants from the UK Medical Research Council and the Brains for Dementia Research, a joint venture between Alzheimer’s Society and Alzheimer’s Research UK. | en |
dc.description.abstract | 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 mutations increase susceptibility to develop LBD. We investigated relationships between LBD-specific glucocerebrosidase deficits, GBA-related pathways, and α-synuclein levels in brain tissue from LBD and controls, with and without GBA mutations. We show that LBD is characterised by altered sphingolipid metabolism with prominent elevation of ceramide species, regardless of GBA mutations. 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 CSF and frontal cortex were heavily loaded with ceramides and neurodegeneration-linked proteins including alpha-synuclein and tau. Our in vitro studies demonstrate that LBD EV constitute a “pathological package” capable of inducing aggregation of wild-type alpha-synuclein, mediated 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, and that GBA mutations likely accelerate the pathological process occurring in sporadic LBD through endolysosomal deficiency. | |
dc.format.extent | 24 | |
dc.language.iso | eng | |
dc.relation.ispartof | Acta Neuropathologica | en |
dc.rights | Copyright © The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. | en |
dc.subject | Lewy body disorders | en |
dc.subject | Glucocerebrosidase | en |
dc.subject | Extracellular vesicles | en |
dc.subject | Exosomes | en |
dc.subject | Alpha-synuclein | en |
dc.subject | Ceramide | en |
dc.subject | QH301 Biology | en |
dc.subject | RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry | en |
dc.subject | 3rd-DAS | en |
dc.subject.lcc | QH301 | en |
dc.subject.lcc | RC0321 | en |
dc.title | Altered ceramide metabolism is a feature in the extracellular vesicle-mediated spread of alpha-synuclein in Lewy body disorders | en |
dc.type | Journal article | en |
dc.description.version | Publisher PDF | en |
dc.contributor.institution | University of St Andrews. School of Medicine | en |
dc.contributor.institution | University of St Andrews. Biomedical Sciences Research Complex | en |
dc.contributor.institution | University of St Andrews. Cellular Medicine Division | en |
dc.identifier.doi | https://doi.org/10.1007/s00401-021-02367-3 | |
dc.description.status | Peer reviewed | en |
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