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Analysis of α-synuclein species enriched from cerebral cortex of humans with sporadic dementia with Lewy bodies

Sanderson, JB; De, S; Jiang, H; Rovere, M; Jin, M; Zaccagnini, L; Hays Watson, A; ... Bartels, T; + view all (2020) Analysis of α-synuclein species enriched from cerebral cortex of humans with sporadic dementia with Lewy bodies. Brain Communications , 2 (1) , Article fcaa010. 10.1093/braincomms/fcaa010. Green open access

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Abstract

Since researchers identified α-synuclein as the principal component of Lewy bodies and Lewy neurites, studies have suggested that it plays a causative role in the pathogenesis of dementia with Lewy bodies and other 'synucleinopathies'. While α-synuclein dyshomeostasis likely contributes to the neurodegeneration associated with the synucleinopathies, few direct biochemical analyses of α-synuclein from diseased human brain tissue currently exist. In this study, we analysed sequential protein extracts from a substantial number of patients with neuropathological diagnoses of dementia with Lewy bodies and corresponding controls, detecting a shift of cytosolic and membrane-bound physiological α-synuclein to highly aggregated forms. We then fractionated aqueous extracts (cytosol) from cerebral cortex using non-denaturing methods to search for soluble, disease-associated high molecular weight species potentially associated with toxicity. We applied these fractions and corresponding insoluble fractions containing Lewy-type aggregates to several reporter assays to determine their bioactivity and cytotoxicity. Ultimately, high molecular weight cytosolic fractions enhances phospholipid membrane permeability, while insoluble, Lewy-associated fractions induced morphological changes in the neurites of human stem cell-derived neurons. While the concentrations of soluble, high molecular weight α-synuclein were only slightly elevated in brains of dementia with Lewy bodies patients compared to healthy, age-matched controls, these observations suggest that a small subset of soluble α-synuclein aggregates in the brain may drive early pathogenic effects, while Lewy body-associated α-synuclein can drive neurotoxicity.

Type: Article
Title: Analysis of α-synuclein species enriched from cerebral cortex of humans with sporadic dementia with Lewy bodies
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/braincomms/fcaa010
Publisher version: https://doi.org/10.1093/braincomms/fcaa010
Language: English
Additional information: Copyright © The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Lewy body dementia, human tissue, neurotoxicity, α-synuclein
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > UK Dementia Research Institute
URI: https://discovery.ucl.ac.uk/id/eprint/10103646
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