<i>Drosophila</i> Histone Deacetylase 6 Protects Dopaminergic Neurons against α-Synuclein Toxicity by Promoting Inclusion Formation

Abstract

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.