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Lookup NU author(s): Dr Marzena Kurzawa-Akanbi, Rachel Heap, Professor Matthias TrostORCiD, Dr Preeti Singh, Dr Florence Burte, Professor Ian McKeith, Dr Christopher Morris
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
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.
Author(s): Kurzawa-Akanbi M, Tammireddy S, Fabrik I, Gliaudelyte L, Doherty MK, Heap R, Matecko-Burmann I, Burmann BM, Trost M, Lucocq JM, Gherman AV, Fairfoul G, Singh P, Burte F, Green A, McKeith IG, Härtlova A, Whitfield PD, Morris CM
Publication type: Article
Publication status: Published
Journal: Acta Neuropathologica
Year: 2021
Volume: 142
Pages: 961-984
Print publication date: 01/12/2021
Online publication date: 13/09/2021
Acceptance date: 01/09/2021
Date deposited: 29/03/2022
ISSN (print): 0001-6322
ISSN (electronic): 1432-0533
Publisher: Springer
URL: https://doi.org/10.1007/s00401-021-02367-3
DOI: 10.1007/s00401-021-02367-3
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