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

Kurzawa-Akanbi, M. et al. (2021) Altered ceramide metabolism is a feature in the extracellular vesicle-mediated spread of alpha-synuclein in Lewy body disorders. Acta Neuropathologica, 142(6), pp. 961-984. (doi: 10.1007/s00401-021-02367-3) (PMID:34514546)

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. [Abstract copyright: © 2021. The Author(s).]

• Item Type: Articles
• Keywords: Lewy body disorders, extracellular vesicles, glucocerebrosidase, ceramide, alpha-synuclein, exosomes.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Whitfield, Mr Phil
• Authors: 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., and Morris, C. M.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Acta Neuropathologica
• Publisher: Springer
• ISSN: 0001-6322
• ISSN (Online): 1432-0533
• Published Online: 13 September 2021
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Acta Neuropathologica 142(6): 961-984
• Publisher Policy: Reproduced under a Creative Commons licence