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Kurzawa-Akanbi M, Tammireddy S, Fabrik I, et al. Altered ceramide metabolism is a feature in the extracellular vesicle-mediated spread of alpha-synuclein in Lewy body disorders. Acta Neuropathol. 2021;142(6):961-984doi: 10.1007/s00401-021-02367-3.
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, 142(6), 961-984. https://doi.org/10.1007/s00401-021-02367-3
Kurzawa-Akanbi, Marzena, et al. "Altered ceramide metabolism is a feature in the extracellular vesicle-mediated spread of alpha-synuclein in Lewy body disorders." Acta neuropathologica vol. 142,6 (2021): 961-984. doi: https://doi.org/10.1007/s00401-021-02367-3
Kurzawa-Akanbi M, Tammireddy S, Fabrik I, Gliaudelytė L, Doherty MK, Heap R, Matečko-Burmann I, Burmann BM, Trost M, Lucocq JM, Gherman AV, Fairfoul G, Singh P, Burté F, Green A, McKeith IG, Härtlova 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. 2021 Dec;142(6):961-984. doi: 10.1007/s00401-021-02367-3. Epub 2021 Sep 13. PMID: 34514546; PMCID: PMC8568874.
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Acta Neuropathol. 2021 Dec;142(6):961-984. doi: 10.1007/s00401-021-02367-3. Epub 2021 Sep 13.

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

Acta neuropathologica

Marzena Kurzawa-Akanbi, Seshu Tammireddy, Ivo Fabrik, Lina Gliaudelytė, Mary K Doherty, Rachel Heap, Irena Matečko-Burmann, Björn M Burmann, Matthias Trost, John M Lucocq, Anda V Gherman, Graham Fairfoul, Preeti Singh, Florence Burté, Alison Green, Ian G McKeith, Anetta Härtlova, Phillip D Whitfield, Christopher M Morris

Affiliations

  1. Biosciences Institute, International Centre for Life, Newcastle University, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK. [email protected].
  2. Lipidomics Research Facility, Division of Biomedical Sciences, Centre for Health Science, University of the Highlands and Islands, Inverness, UK.
  3. Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, 405 30, Göteborg, Sweden.
  4. Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
  5. Biosciences Institute, International Centre for Life, Newcastle University, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK.
  6. Department of Psychiatry and Neurochemistry, University of Gothenburg, 405 30, Göteborg, Sweden.
  7. Department of Chemistry and Molecular Biology, University of Gothenburg, 405 30, Göteborg, Sweden.
  8. Schools of Medicine and Biology, Medical and Biological Sciences Building, University of St Andrews, North Haugh, St Andrews, UK.
  9. College of Medicine and Veterinary Medicine, The University of Edinburgh, Little France Crescent, Edinburgh, EH16 4TJ, UK.
  10. The National CJD Research & Surveillance Unit, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, EH16 4SB, UK.
  11. Department of Immunology and Microbiology, University of Gothenburg, 405 30, Göteborg, Sweden.
  12. Glasgow Polyomics, College of Medical, Veterinary and Life Sciences, University of Glasgow, Garscube Campus, Glasgow, G61 1QH, UK.

PMID: 34514546 PMCID: PMC8568874 DOI: 10.1007/s00401-021-02367-3

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.

© 2021. The Author(s).

Keywords: Alpha-synuclein; Ceramide; Exosomes; Extracellular vesicles; Glucocerebrosidase; Lewy body disorders

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