National Laboratory of Macromolecules and State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Mol Biol Cell. 2010 Jul 1;21(13):2128-37. doi: 10.1091/mbc.e10-03-0200. Epub 2010 May 5.
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 alpha-synuclein inclusions by using a Drosophila PD model constructed by ectopic expression of human alpha-synuclein. Depletion of dHDAC6 significantly enhances the effects caused by ectopic expression of alpha-synuclein, namely, loss of DA neurons, retinal degeneration, and locomotor dysfunction. Expression of alpha-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 alpha-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 alpha-synuclein. We propose that alpha-synuclein inclusion formation in the presence of dHDAC6 protects DA neurons from being damaged by oligomers, which may uncover a common mechanism for synucleinopathies.
帕金森病（PD）与多巴胺能（DA）神经元的进行性退化有关。我们首次报道，果蝇组蛋白去乙酰化酶 6（dHDAC6）在通过异位表达人α-突触核蛋白构建的果蝇 PD 模型中，对 DA 神经元的保护和α-突触核蛋白包涵体的形成起着关键作用。dHDAC6 的耗竭显著增强了α-突触核蛋白异位表达引起的影响，即 DA 神经元的丧失、视网膜变性和运动功能障碍。α-突触核蛋白在 DA 神经元中的表达导致 dHDAC6 突变果蝇脑中的包涵体比野生型果蝇中少。相反，过表达 dHDAC6 能够抑制α-突触核蛋白诱导的 DA 神经元丧失和视网膜变性，并促进包涵体的形成。此外，dHDAC6 的突变增强了寡聚物的积累，寡聚物被认为是α-突触核蛋白的一种毒性形式。我们提出，dHDAC6 存在时α-突触核蛋白包涵体的形成可以保护 DA 神经元免受寡聚物的损伤，这可能揭示了一种突触核蛋白病的共同机制。
