Ettle, Benjamin and Kerman, Bilal E. and Valera, Elvira and Gillmann, Clarissa and Schlachetzki, Johannes C. M. and Reiprich, Simone and Buettner, Christian and Ekici, Arif B. and Reis, Andre and Wegner, Michael and Baeuerle, Tobias and Riemenschneider, Markus J. and Masliah, Eliezer and Gage, Fred H. and Winkler, Juergen (2016) alpha-Synuclein-induced myelination deficit defines a novel interventional target for multiple system atrophy. ACTA NEUROPATHOLOGICA, 132 (1). pp. 59-75. ISSN 0001-6322, 1432-0533
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled 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 |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Abteilung für Neuropathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 09 Apr 2019 11:52 |
| Last Modified: | 09 Apr 2019 11:52 |
| URI: | https://pred.uni-regensburg.de/id/eprint/3699 |
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