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首页> 外文期刊>BMC Neuroscience >Limited effects of dysfunctional macroautophagy on the accumulation of extracellularly derived α-synuclein in oligodendroglia: implications for MSA pathogenesis
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Limited effects of dysfunctional macroautophagy on the accumulation of extracellularly derived α-synuclein in oligodendroglia: implications for MSA pathogenesis

机译：功能失调的巨噬细胞自噬对少突胶质细胞外衍生α-突触核蛋白积累的有限影响：对MSA发病机制的影响

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The progressive neurodegenerative disorder multiple system atrophy (MSA) is characterized by α-synuclein-positive (oligodendro-) glial cytoplasmic inclusions (GCIs). A connection between the abnormal accumulation of α-synuclein in GCIs and disease initiation and progression has been postulated. Mechanisms involved in the formation of GCIs are unclear. Abnormal uptake of α-synuclein from extracellular space, oligodendroglial overexpression of α-synuclein, and/or dysfunctional protein degradation including macroautophagy have all been discussed. In the current study, we investigated whether dysfunctional macroautophagy aggravates accumulation of extracellular α-synuclein in the oligodendroglia. We show that oligodendroglia uptake monomeric and fibrillar extracellular α-synuclein. Blocking macroautophagy through bafilomycin A1 treatment or genetic knockdown of LC3B does not consistently change the level of incorporated α-synuclein in oligodendroglia exposed to extracellular soluble/monomeric or fibrillar α-synuclein, however leads to higher oxidative stress in combination with fibrillar α-synuclein treatment. Finally, we detected no evidence for GCI-like formation resulting from dysfunctional macroautophagy in oligodendroglia using confocal microscopy. In summary, isolated dysfunctional macroautophagy is not sufficient to enhance abnormal accumulation of uptaken α-synuclein in vitro, but may lead to increased production of reactive oxygen species in the presence of fibrillar α-synuclein. Multiple complementary pathways are likely to contribute to GCI formation in MSA.
机译：进行性神经退行性疾病多系统萎缩症（MSA）的特征在于α-突触核蛋白阳性（少突胶质）神经胶质细胞质包涵体（GCI）。推测GCI中α-突触核蛋白的异常积累与疾病的发生和发展之间存在联系。目前尚不清楚参与GCI形成的机制。已经讨论了从细胞外空间异常摄取α-突触核蛋白，少突胶质细胞过度表达α-突触核蛋白和/或功能紊乱的蛋白质降解，包括巨噬细胞吞噬。在当前的研究中，我们调查了功能异常的巨噬细胞吞噬功能是否会加剧少突胶质细胞外α-突触核蛋白的积累。我们显示少突胶质细胞摄取单体和纤维状细胞外α-突触核蛋白。通过bafilomycin A1治疗或LC3B的基因敲低来阻断巨噬细胞自噬并不能始终改变暴露于细胞外可溶性/单体或原纤维α-突触核蛋白的少突胶质细胞中α-突触核蛋白的掺入水平，但是与原纤维α-突触核蛋白治疗相结合会导致更高的氧化应激。最后，我们没有发现使用共聚焦显微镜观察到少突胶质细胞自噬功能异常引起的GCI样形成的证据。总之，孤立的功能失调的巨噬细胞自噬不足以增强体外摄取的α-突触核蛋白的异常积累，但在存在纤维状α-突触核蛋白的情况下可能导致活性氧的产生增加。多种互补途径可能有助于MSA中GCI的形成。

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