Taylor-Whiteley, TR, Le Maitre, CL, Duce, JA orcid.org/0000-0002-8762-2245 et al. (2 more authors) (2019) Recapitulating Parkinson's disease pathology in a three-dimensional human neural cell culture model. Disease Models & Mechanisms, 12 (4). dmm038042. ISSN 1754-8403
Abstract
Extensive loss of dopaminergic neurons and aggregation of the protein α-synuclein into ubiquitin-positive Lewy bodies represents a major neuropathological hallmark of Parkinson's disease (PD). At present, the generation of large nuclear-associated Lewy bodies from endogenous wild-type α-synuclein, translationally regulated under its own promoter in human cell culture models, requires costly and time-consuming protocols. Here, we demonstrate that fully differentiated human SH-SY5Y neuroblastoma cells grown in three-dimensional cell culture develop Lewy-body-like pathology upon exposure to exogenous α-synuclein species. In contrast to most cell- and rodent-based PD models, which exhibit multiple diffuse α-synuclein aggregates throughout the cytoplasm, a single large nuclear inclusion that is immunopositive for α-synuclein and ubiquitin is rapidly obtained in our model. This was achieved without the need for overexpression of α-synuclein or genetic modification of the cell line. However, phosphorylation of α-synuclein within these inclusions was not observed. The system described here provides an ideal tool to screen compounds to therapeutically intervene in Lewy body formation, and to investigate the mechanisms involved in disease progression in synucleinopathies.
Metadata
Item Type: | Article |
---|---|
Authors/Creators: |
|
Copyright, Publisher and Additional Information: | (c) 2019. Published by The Company of Biologists Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. |
Keywords: | 3D cell culture, Amyloid, Lewy body, Oligomer, Parkinson’s, Synuclein |
Dates: |
|
Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Biomedical Sciences (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 23 May 2019 15:04 |
Last Modified: | 23 May 2019 15:04 |
Status: | Published |
Publisher: | Company of Biologists |
Identification Number: | 10.1242/dmm.038042 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:146249 |