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dc.contributor.authorValdinocci, Dario
dc.contributor.authorGrant, Gary D
dc.contributor.authorDickson, Tracey C
dc.contributor.authorPountney, Dean L
dc.date.accessioned2019-06-07T01:32:14Z
dc.date.available2019-06-07T01:32:14Z
dc.date.issued2018
dc.identifier.issn1044-7431
dc.identifier.doi10.1016/j.mcn.2018.04.006
dc.identifier.urihttp://hdl.handle.net/10072/380782
dc.description.abstractMultiple 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.
dc.description.peerreviewedYes
dc.languageEnglish
dc.publisherElsevier
dc.publisher.placeUnited States
dc.relation.ispartofpagefrom80
dc.relation.ispartofpageto94
dc.relation.ispartofjournalMolecular and Cellular Neuroscience
dc.relation.ispartofvolume89
dc.subject.fieldofresearchNeurosciences not elsewhere classified
dc.subject.fieldofresearchNeurosciences
dc.subject.fieldofresearchCognitive Sciences
dc.subject.fieldofresearchPsychology
dc.subject.fieldofresearchcode110999
dc.subject.fieldofresearchcode1109
dc.subject.fieldofresearchcode1702
dc.subject.fieldofresearchcode1701
dc.titleEpothilone D inhibits microglia-mediated spread of alpha-synuclein aggregates
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
dcterms.licensehttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.description.versionPost-print
gro.facultyGriffith Health, School of Medical Science
gro.rights.copyright© 2018 Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International Licence (http://creativecommons.org/licenses/by-nc-nd/4.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, providing that the work is properly cited.
gro.hasfulltextFull Text
gro.griffith.authorGrant, Gary D.
gro.griffith.authorPountney, Dean L.
gro.griffith.authorValdinocci, Dario


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