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Mol Biol Cell. 2010 Jul 1;21(13):2128-37. doi: 10.1091/mbc.E10-03-0200. Epub 2010 May 5.

Drosophila histone deacetylase 6 protects dopaminergic neurons against {alpha}-synuclein toxicity by promoting inclusion formation.

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  • 1National Laboratory of Macromolecules and State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.


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.

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