Journal
ACTA NEUROPATHOLOGICA
Volume 132, Issue 1, Pages 59-75Publisher
SPRINGER
DOI: 10.1007/s00401-016-1572-y
Keywords
Multiple system atrophy; Oligodendrocytes; Oligodendrocyte progenitor cells; Myelin; alpha-Synuclein
Categories
Funding
- Interdisciplinary Center for Clinical Research (IZKF Erlangen) [TP E18]
- Bavarian State Ministry of Education and Culture, Science and Arts of the Bavarian Research Network Induced Pluripotent Stem Cells (ForIPS)
- Deutsche Forschungsgemeinschaft (DFG) [INST 410/45-1 FUGG, SCHL 21021-1]
- NIH [AG5131, AG18440, NS092803]
- G. Harold and Leila Y. Mathers Charitable Foundation
- JPB Foundation
- Leona M. and Harry B. Helmsley Charitable Trust
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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.
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