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Epothilone D inhibits microglia-mediated spread of alpha-synuclein aggregates
Citation
Valdinocci, D and Grant, GD and Dickson, TC and Pountney, DL, Epothilone D inhibits microglia-mediated spread of alpha-synuclein aggregates, Molecular and Cellular Neuroscience, 89 pp. 80-94. ISSN 1044-7431 (2018) [Refereed Article]
Copyright Statement
© 2018 Elsevier Inc. All rights reserved.
DOI: doi:10.1016/j.mcn.2018.04.006
Abstract
Multiple System Atrophy (MSA) is a progressive neurodegenerative disease characterized by chronic neuroinflammation and widespread α-synuclein (α-syn) cytoplasmic inclusions. Neuroinflammation associated with microglial cells is typically located in brain regions with α-syn deposits. The potential link between microglial cell migration and the transport of pathological α-syn protein in MSA was investigated. Qualitative analysis via immunofluorescence of MSA cases (n = 4) revealed microglial cells bearing α-syn inclusions distal from oligodendrocytes bearing α-syn cytoplasmic inclusions, as well as close interactions between microglia and oligodendrocytes bearing α-syn, suggestive of a potential transfer mechanism between microglia and α-syn bearing cells in MSA and the possibility of microglia acting as a mobile vehicle to spread α-syn between anatomically connected brain regions. Further In vitro experiments using microglial-like differentiated THP-1 cells were conducted to investigate if microglial cells could act as potential transporters of α-syn. Monomeric or aggregated α-syn was immobilized at the centre of glass coverslips and treated with either cell free medium, undifferentiated THP-1 cells or microglial-like phorbol-12-myristate-13-acetate differentiated THP-1 cells (48 h; n = 3). A significant difference in residual immobilized α-syn density was observed between cell free controls and differentiated (p = 0.016) as well as undifferentiated and differentiated THP-1 cells (p = 0.032) when analysed by quantitative immunofluorescence. Furthermore, a significantly greater proportion of differentiated cells were observed bearing α-syn aggregates distal from the immobilized protein than their non-differentiated counterparts (p = 0.025). Similar results were observed with Highly Aggressive Proliferating Immortalised (HAPI) microglial cells, with cells exposed to aggregated α-syn yielding lower residual immobilized α-syn (p = 0.004) and a higher proportion of α-syn positive distal cells (p = 0.001) than cells exposed to monomeric α-syn. Co-treatment of THP-1 groups with the tubulin depolymerisation inhibitor, Epothilone D (EpoD; 10 nM), was conducted to investigate if inhibition of microtubule activity had an effect on cell migration and residual immobilized α-syn density. There was a significant increase in both residual immobilized α-syn between EpoD treated and non-treated differentiated cells exposed to monomeric (p = 0.037) and aggregated (p = 0.018) α-syn, but not with undifferentiated cells. Differentiated THP-1 cells exposed to immobilized aggregated α-syn showed a significant difference in the proportion of distal aggregate bearing cells between EpoD treated and untreated (p = 0.027). The results suggest microglia could play a role in α-syn transport in MSA, a role which could potentially be inhibited therapeutically by EpoD.
Item Details
Item Type: | Refereed Article |
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Keywords: | multiple system atrophy, alpha-synuclein, microglia, epothilione D, microtubule |
Research Division: | Biomedical and Clinical Sciences |
Research Group: | Neurosciences |
Research Field: | Neurology and neuromuscular diseases |
Objective Division: | Health |
Objective Group: | Clinical health |
Objective Field: | Clinical health not elsewhere classified |
UTAS Author: | Dickson, TC (Professor Tracey Dickson) |
ID Code: | 126740 |
Year Published: | 2018 |
Web of Science® Times Cited: | 11 |
Deposited By: | Menzies Institute for Medical Research |
Deposited On: | 2018-06-21 |
Last Modified: | 2019-02-25 |
Downloads: | 0 |
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