Item type: | Article | ||||
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Journal or Publication Title: | Acta Neuropathologica | ||||
Publisher: | Springer | ||||
Place of Publication: | NEW YORK | ||||
Volume: | 132 | ||||
Number of Issue or Book Chapter: | 1 | ||||
Page Range: | pp. 59-75 | ||||
Date: | 2016 | ||||
Institutions: | Medicine > Abteilung für Neuropathologie | ||||
Identification Number: |
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Keywords: | GLIAL CYTOPLASMIC INCLUSIONS; MOUSE MODEL; OLIGODENDROCYTE PROMOTER; IN-VITRO; DEGENERATION; EXPRESSION; PATHOPHYSIOLOGY; REMYELINATION; MATURATION; GENERATION; Multiple system atrophy; Oligodendrocytes; Oligodendrocyte progenitor cells; Myelin; alpha-Synuclein | ||||
Dewey Decimal Classification: | 600 Technology > 610 Medical sciences Medicine | ||||
Status: | Published | ||||
Refereed: | Yes, this version has been refereed | ||||
Created at the University of Regensburg: | Yes | ||||
Item ID: | 42668 |
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 alpha-synuclein accumulation in oligodendrocytes, but underlying pathomechanisms are poorly understood. Here, we analyzed the impact of oligodendrocytic ...

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 alpha-synuclein accumulation in oligodendrocytes, but underlying pathomechanisms are poorly understood. Here, we analyzed the impact of oligodendrocytic alpha-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 alpha-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 alpha-synuclein in primary and stem cell-derived oligodendrocytes severely impaired myelin formation, defining a novel alpha-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 alpha-synuclein. Additionally, benztropine restored the alpha-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 alpha-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.
Metadata last modified: 17 Mar 2020 11:34