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

作者：Ettle Benjamin; Kerman Bilal E; Valera Elvira; Gillmann Clarissa; Schlachetzki Johannes C M; Reiprich Simone; Buettner Christian; Ekici Arif B; Reis Andre; Wegner Michael; Baeuerle Tobias; Riemenschneider Markus J; Masliah Eliezer; Gage Fred H; Winkler Juergen^*

来源：Acta Neuropathologica, 2016, 132(1): 59-75.

DOI：10.1007/s00401-016-1572-y

• Multiple system atrophy
• Oligodendrocytes
• Oligodendrocyte progenitor cells
• Myelin
• alpha-Synuclein

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.

• 出版日期2016-7