?-Synuclein-induced myelination deficit defines a novel interventional target for multiple system atrophy

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dc.authorid0000-0003-1106-3288
dc.contributor.authorEttle, Benjamin
dc.contributor.authorKerman, Bilal Ersen
dc.contributor.authorValera-Martin, Elvira
dc.contributor.authorGillmann, Clarissa
dc.contributor.authorSchlachetzki, Johannes Carolus Magnus
dc.contributor.authorReiprich, Simone
dc.contributor.authorBüttner, Christian
dc.contributor.authorEkici, Arif Bülent
dc.contributor.authorReis, André
dc.contributor.authorWegner, Michael M.
dc.contributor.authorBaüerle, Tobias J.
dc.contributor.authorRiemenschneider, Markus Johannes
dc.contributor.authorMasliah, Eliezer
dc.contributor.authorGage, Fred H.
dc.contributor.authorWinkler, Jürgen
dc.date.accessioned10.07.201910:49:13
dc.date.accessioned2019-07-10T19:35:22Z
dc.date.available10.07.201910:49:14
dc.date.available2019-07-10T19:35:22Z
dc.date.issued2016
dc.departmentİstanbul Medipol Üniversitesi, Rektörlük, Rejeneratif ve Restoratif Tıp Araştırmaları Merkezi (REMER)
dc.description.abstractMultiple system atrophy (MSA) is a rare atypical parkinsonian disorder characterized by a rapidly progressing clinical course and at present without any efficient therapy. Neuropathologically, myelin loss and neurodegeneration are associated with ?-synuclein accumulation in oligodendrocytes, but underlying pathomechanisms are poorly understood. Here, we analyzed the impact of oligodendrocytic ?-synuclein on the formation of myelin sheaths to define a potential interventional target for MSA. Post-mortem analyses of MSA patients and controls were performed to quantify myelin and oligodendrocyte numbers. As pre-clinical models, we used transgenic MSA mice, a myelinating stem cell-derived oligodendrocyte-neuron co-culture, and primary oligodendrocytes to determine functional consequences of oligodendrocytic ?-synuclein overexpression on myelination. We detected myelin loss accompanied by preserved or even increased numbers of oligodendrocytes in post-mortem MSA brains or transgenic mouse forebrains, respectively, indicating an oligodendrocytic dysfunction in myelin formation. Corroborating this observation, overexpression of ?-synuclein in primary and stem cell-derived oligodendrocytes severely impaired myelin formation, defining a novel ?-synuclein-linked pathomechanism in MSA. We used the pro-myelinating activity of the muscarinic acetylcholine receptor antagonist benztropine to analyze the reversibility of the myelination deficit. Transcriptome profiling of primary pre-myelinating oligodendrocytes demonstrated that benztropine readjusts myelination-related processes such as cholesterol and membrane biogenesis, being compromised by oligodendrocytic ?-synuclein. Additionally, benztropine restored the ?-synuclein-induced myelination deficit of stem cell-derived oligodendrocytes. Strikingly, benztropine also ameliorated the myelin deficit in transgenic MSA mice, resulting in a prevention of neuronal cell loss. In conclusion, this study defines the ?-synuclein-induced myelination deficit as a novel and crucial pathomechanism in MSA. Importantly, the reversible nature of this oligodendrocytic dysfunction opens a novel avenue for an intervention in MSA.
dc.identifier.citationEttle, B., Kerman, B. E., Valera-Martin, E., Gillmann, C., Schlachetzki, J. C. M., Reiprich, S. ... Winkler, J. (2016). ?-Synuclein-induced myelination deficit defines a novel interventional target for multiple system atrophy. Acta Neuropathologica, 132(1), 59-75. https://dx.doi.org/10.1007/s00401-016-1572-y
dc.identifier.doi10.1007/s00401-016-1572-y
dc.identifier.endpage75
dc.identifier.issn0001-6322
dc.identifier.issn1432-0533
dc.identifier.issue1
dc.identifier.scopusqualityQ1
dc.identifier.startpage59
dc.identifier.urihttps://hdl.handle.net/20.500.12511/744
dc.identifier.urihttps://dx.doi.org/10.1007/s00401-016-1572-y
dc.identifier.volume132
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherSpringer
dc.relation.ispartofActa Neuropathologicaen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectMultiple System Atrophy
dc.subjectMyelin
dc.subjectOligodendrocyte Progenitor Cells
dc.subjectOligodendrocytes
dc.subject?-Synuclein
dc.title?-Synuclein-induced myelination deficit defines a novel interventional target for multiple system atrophy
dc.typeArticle

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