dc.contributor.author | Ettle, Benjamin | |
dc.contributor.author | Kerman, Bilal Ersen | |
dc.contributor.author | Valera-Martin, Elvira | |
dc.contributor.author | Gillmann, Clarissa | |
dc.contributor.author | Schlachetzki, Johannes Carolus Magnus | |
dc.contributor.author | Reiprich, Simone | |
dc.contributor.author | Büttner, Christian | |
dc.contributor.author | Ekici, Arif Bülent | |
dc.contributor.author | Reis, André | |
dc.contributor.author | Wegner, Michael M. | |
dc.contributor.author | Baüerle, Tobias J. | |
dc.contributor.author | Riemenschneider, Markus Johannes | |
dc.contributor.author | Masliah, Eliezer | |
dc.contributor.author | Gage, Fred H. | |
dc.contributor.author | Winkler, Jürgen | |
dc.date.accessioned | 10.07.201910:49:13 | |
dc.date.accessioned | 2019-07-10T19:35:22Z | |
dc.date.available | 10.07.201910:49:14 | |
dc.date.available | 2019-07-10T19:35:22Z | |
dc.date.issued | 2016 | en_US |
dc.identifier.citation | Ettle, B., Kerman, B. E., Valera-Martin, E., Gillmann, C., Schlachetzki, J. C. M., Reiprich, S. ... Winkler, J. (2016). α-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 | en_US |
dc.identifier.issn | 0001-6322 | |
dc.identifier.issn | 1432-0533 | |
dc.identifier.uri | https://hdl.handle.net/20.500.12511/744 | |
dc.identifier.uri | https://dx.doi.org/10.1007/s00401-016-1572-y | |
dc.description.abstract | Multiple 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. | en_US |
dc.language.iso | eng | en_US |
dc.publisher | Springer | en_US |
dc.rights | info:eu-repo/semantics/openAccess | en_US |
dc.subject | Multiple System Atrophy | en_US |
dc.subject | Myelin | en_US |
dc.subject | Oligodendrocyte Progenitor Cells | en_US |
dc.subject | Oligodendrocytes | en_US |
dc.subject | α-Synuclein | en_US |
dc.title | α-Synuclein-induced myelination deficit defines a novel interventional target for multiple system atrophy | en_US |
dc.type | article | en_US |
dc.relation.ispartof | Acta Neuropathologica | en_US |
dc.department | İstanbul Medipol Üniversitesi, Rektörlük, Rejeneratif ve Restoratif Tıp Araştırmaları Merkezi (REMER) | en_US |
dc.authorid | 0000-0003-1106-3288 | en_US |
dc.identifier.volume | 132 | en_US |
dc.identifier.issue | 1 | en_US |
dc.identifier.startpage | 59 | en_US |
dc.identifier.endpage | 75 | en_US |
dc.relation.publicationcategory | Makale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı | en_US |
dc.identifier.doi | 10.1007/s00401-016-1572-y | en_US |
dc.identifier.wosquality | Q1 | en_US |
dc.identifier.scopusquality | Q1 | en_US |