Toggle Main Menu Toggle Search

Open Access padlockePrints

Altered ceramide metabolism is a feature in the extracellular vesicle-mediated spread of alpha-synuclein in Lewy body disorders

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

Downloads


Licence

This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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.


Publication metadata

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


Altmetrics

Altmetrics provided by Altmetric


Funding

Funder referenceFunder name
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.
Newcastle University TEM Services acknowledge BBSRC support (Grant code BB/R013942/1).
Lewy Body Society and the Michael J. Fox Foundation for Parkinson’s Research.
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.
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.

Share