α-Synuclein-induced myelination deficit defines a novel interventional target for multiple system atrophy.
α-Synuclein-induced myelination deficit defines a novel interventional target for multiple system atrophy.
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DOI：
10.1007/s00401-016-1572-y
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发表时间：
2016-07
影响因子：
12.7
通讯作者：
Winkler J
中科院分区：
文献类型：
--
作者：
Ettle B;Kerman BE;Valera E;Gillmann C;Schlachetzki JC;Reiprich S;Büttner C;Ekici AB;Reis A;Wegner M;Bäuerle T;Riemenschneider MJ;Masliah E;Gage FH;Winkler J
多系统萎缩症是一种罕见的非典型帕金森病，其特征是临床进展迅速，目前尚无有效的治疗方法。在神经病理学上，髓鞘丢失和神经变性与少突胶质细胞中α-突触核蛋白积累相关，但对潜在的病理机制知之甚少。在这里，我们分析了少突胶质细胞α-突触核蛋白对髓鞘形成的影响，以确定MSA的潜在干预靶点。对MSA患者和对照组进行尸检分析，以量化髓鞘和少突胶质细胞的数量。作为临床前模型，我们使用转基因MSA小鼠、髓鞘形成干细胞衍生的少突胶质细胞-神经元共培养物和原代少突胶质细胞来确定少突胶质细胞α-突触核蛋白过表达对髓鞘形成的功能后果。我们检测到髓鞘损失伴随着保存或甚至增加的少突胶质细胞的数量在死后MSA大脑或转基因小鼠前脑，分别表明髓鞘形成少突胶质细胞功能障碍。证实了这一观察结果，α-突触核蛋白在原代和干细胞来源的少突胶质细胞中的过表达严重损害了髓鞘形成，定义了MSA中新的α-突触核蛋白相关的病理机制。我们使用毒蕈碱型乙酰胆碱受体拮抗剂苯扎托品的前髓鞘形成活性来分析髓鞘形成缺陷的可逆性。原代前髓鞘少突胶质细胞的转录组分析表明，苯托品重新调整髓鞘形成相关过程，如胆固醇和膜生物合成，受到少突胶质细胞α-突触核蛋白的影响。此外，benztropine恢复了α-突触核蛋白诱导的干细胞来源的少突胶质细胞髓鞘形成缺陷。引人注目的是，benztropine还改善了转基因MSA小鼠的髓鞘缺陷，从而防止神经元细胞丢失。总之，本研究将α-突触核蛋白诱导的髓鞘形成缺陷定义为MSA的一种新的和关键的病理机制。重要的是，这种少突胶质细胞功能障碍的可逆性为干预MSA开辟了一条新途径。
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 α-synuclein accumulation in oligodendrocytes, but underlying pathomechanisms are poorly understood. Here, we analyzed the impact of oligodendrocytic α-synuclein on the formation of myelin sheaths in order 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 α-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 α-synuclein in primary and stem cell-derived oligodendrocytes severely impaired myelin formation, defining a novel α-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 α-synuclein. Additionally, benztropine restored the α-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 α-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.