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首页> 外文期刊>Molecular biology of the cell >A Highlights from MBoC Selection: Drosophila Histone Deacetylase 6 Protects Dopaminergic Neurons against α-Synuclein Toxicity by Promoting Inclusion Formation
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A Highlights from MBoC Selection: Drosophila Histone Deacetylase 6 Protects Dopaminergic Neurons against α-Synuclein Toxicity by Promoting Inclusion Formation

机译:MBoC选择的亮点:果蝇组蛋白去乙酰化酶6通过促进包涵体形成保护多巴胺能神经元免受α-突触核蛋白的毒性。

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摘要

Parkinson's disease (PD) is associated with progressive degeneration of dopaminergic (DA) neurons. We report for the first time that the Drosophila histone deacetylase 6 (dHDAC6) plays a critical role in the protection of DA neurons and the formation of α-synuclein inclusions by using a Drosophila PD model constructed by ectopic expression of human α-synuclein. Depletion of dHDAC6 significantly enhances the effects caused by ectopic expression of α-synuclein, namely, loss of DA neurons, retinal degeneration, and locomotor dysfunction. Expression of α-synuclein in the DA neurons leads to fewer inclusions in the brains of dHDAC6 mutant flies than in wild-type flies. Conversely, overexpression of dHDAC6 is able to suppress the α-synuclein–induced DA neuron loss and retinal degeneration and promote inclusion formation. Furthermore, mutation of dHDAC6 reinforces the accumulation of oligomers that are suggested to be a toxic form of α-synuclein. We propose that α-synuclein inclusion formation in the presence of dHDAC6 protects DA neurons from being damaged by oligomers, which may uncover a common mechanism for synucleinopathies.
机译:帕金森氏病(PD)与多巴胺能(DA)神经元的进行性变性有关。我们首次报告果蝇组蛋白脱乙酰基酶6(dHDAC6)通过使用通过人α-突触核蛋白异位表达构建的果蝇PD模型在保护DA神经元和形成α-突触核蛋白包合物中起关键作用。 dHDAC6的耗竭显着增强了由异位表达的α-突触核蛋白引起的效应,即DA神经元的丧失,视网膜变性和运动功能障碍。与野生型果蝇相比,DA神经元中α-突触核蛋白的表达导致dHDAC6突变果蝇的大脑中更少的内含物。相反,dHDAC6的过表达能够抑制α-突触核蛋白诱导的DA神经元丢失和视网膜变性,并促进包涵体形成。此外,dHDAC6的突变会增强寡聚体的积累,这被认为是α-突触核蛋白的一种毒性形式。我们提出,在存在dHDAC6的情况下,α-突触核蛋白包涵体的形成可以保护DA神经元免受寡聚体的损害,而寡聚体可能揭示了突触核病的常见机制。

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