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

摘要: Multiple system atrophy (MSA) is a rare atypical parkinsonian disorder characterized by rapidly progressing clinical course and at present without any efficient therapy. Neuropathologically, myelin loss neurodegeneration are associated with α-synuclein accumulation in oligodendrocytes, but underlying pathomechanisms poorly understood. Here, we analyzed the impact of oligodendrocytic on formation sheaths to define potential interventional target for MSA. Post-mortem analyses MSA patients controls were performed quantify oligodendrocyte numbers. As pre-clinical models, used transgenic mice, myelinating stem cell-derived oligodendrocyte-neuron co-culture, primary oligodendrocytes determine functional consequences overexpression myelination. We detected accompanied preserved or even increased numbers post-mortem brains mouse forebrains, respectively, indicating an dysfunction formation. Corroborating this observation, severely impaired formation, defining novel α-synuclein-linked pathomechanism pro-myelinating activity muscarinic acetylcholine receptor antagonist benztropine analyze reversibility myelination deficit. Transcriptome profiling pre-myelinating demonstrated that readjusts myelination-related processes such as cholesterol membrane biogenesis, being compromised α-synuclein. Additionally, restored α-synuclein-induced deficit oligodendrocytes. Strikingly, also ameliorated resulting prevention neuronal cell loss. In conclusion, study defines crucial Importantly, reversible nature opens avenue intervention