Kinase activation in multiple system atrophy

多系统萎缩（MSA）是一种病因不明的神经退行性疾病， 病理生理学MSA是一种独特的蛋白质病，其中α-突触核蛋白优先在细胞中积累。 少突胶质细胞而不是神经元。累积的α-突触核蛋白，称为胶质细胞胞质内含物 (GCI)，被认为会引起少突胶质细胞功能的变化，如神经营养支持减少， 脱髓鞘导致神经变性我们已经开发了新的大鼠和非人灵长类动物（NHP） 使用新的胶质少突胶质细胞营养因子在少突胶质细胞中表达α-突触核蛋白的MSA模型 腺相关病毒（AAV）载体，Olig 001。组织学分析显示Oligo 01广泛表达， 连接的α-突触核蛋白遍布大鼠脑中的纹状体和胼胝体，其中>90%定位于 在神经元或星形胶质细胞中几乎没有表达。该模型还显示脱髓鞘， 胼胝体和纹状体的白色物质束，类似于在患者大脑中观察到的。分析 来自模型动物的GCI显示，它们在Tyr 39和Ser 129处含有疾病特异性磷酸化 这与帕金森病（PD）患者神经元中观察到的α-突触核蛋白的修饰相同。 在MSA模型脑中意外观察到的这些修饰也在MSA患者脑中发现 (see创新）进一步验证了该大鼠模型对MSA发病机制研究的适用性。 虽然MSA和PD都是突触核蛋白病，但长期以来一直认为这些疾病的病理学起源是由于它们的细胞凋亡引起的。 两种疾病是不同的。在MSA中观察到的疾病特异性化学修饰是相同的 在帕金森病中观察到的结果表明，这些不同的疾病之间存在更密切的机制联系。特别是， 由于Abelson酪氨酸激酶c-Abl的激活是PD中的关键疾病起始事件， 由于c-Abl在Tyr 39处的磷酸化，c-Abl可能在MSA中起类似的作用，并且c-Abl的化学抑制可能与c-Abl在MSA中起类似的作用有关。 Abl可能在MSA中具有疾病修饰作用。这表明MSA的治疗可能受益于口服 生物可利用的，脑渗透的c-Abl激酶抑制剂，就像我们在帕金森病中所展示的那样。使用此 新定义的模型的MSA，我们建议，以确定是否MSA有同样的关键依赖c-Abl 在PD中发现的激活，为疾病修饰治疗铺平了道路。

Multiple system atrophy (MSA) is an unrelenting neurodegenerative disorder with an uncertain etiology and pathophysiology. MSA is a unique proteinopathy in which alpha-synuclein accumulates preferentially in oligodendroglia rather than neurons. Accumulated alpha-synuclein, known as a glial cytoplasmic inclusion (GCI), is thought to elicit changes in oligodendrocyte function, such as reduced neurotrophic support and demyelination, leading to neurodegeneration. We have developed novel rat and nonhuman primate (NHP) models of MSA by expressing alpha-synuclein in oligodendroglia using a novel glialoligodendrocyte-trophic adeno-associated virus (AAV) vector, Olig001. Histological analysis showed widespread expression of Oligo01- linked alpha-synuclein throughout the striatum and corpus callosum in rat brain with >90% localized to oligodendroglia and little to no expression in neurons or astrocytes. The model also displays demyelination in the white matter tracts of the corpus callosum and striatum, similar to what is observed in patient brain. Analysis of GCIs from the model animals revealed that they contain disease-specific phosphorylations at Tyr39 and Ser129 that are identical to the modifications of alpha-synuclein seen in neurons of Parkinson's Disease (PD) patients. The unexpected observation of these modifications in MSA model brain were also found in MSA patient brain (see Innovation) further validated the suitability of this rat model for the study of disease mechanism in MSA. While both MSA and PD are synucleinopathies, it has long been thought that the origin of pathology for these two diseases were distinct. The observation of disease-specific chemical modifications in MSA that are identical to what is observed in PD suggests a closer mechanistic linkage between these disparate diseases. In particular, since activation of the Abelson tyrosine kinase c-Abl is a key disease-initiating event in PD that results in phosphorylation at Tyr39, it is possible that c-Abl plays a similar role in MSA and that chemical inhibition of c- Abl could be disease-modifying in MSA. This suggests that treatment for MSA may be benefited by an orally bioavailable, brain-penetrant c-Abl kinase inhibitor, just as we've shown for Parkinson's Disease. Using this newly defined model of MSA, we propose to determine whether MSA has the same critical dependency on c-Abl activation that has been found in PD, paving the way for disease modifying therapy.