Abstract
BackgroundIn contrast to the complexity found in mammals, only two Bcl-2 family genes have been found in Drosophila melanogaster including the pro-cell survival, human Bok-related orthologue, Buffy. The directed expression of α-synuclein, the first gene identified to contribute to inherited forms of Parkinson disease (PD), in the dopaminergic neurons (DA) of flies has provided a robust and well-studied Drosophila model of PD complete with the loss of neurons and accompanying motor defects. To more fully understand the biological basis of Bcl-2 genes in PD, we altered the expression of Buffy in the dopamine producing neurons with and without the expression of α-synuclein, and in the developing neuron-rich eye.ResultsTo alter the expression of Buffy in the dopaminergic neurons of Drosophila, the Ddc-Gal4 transgene was used. The directed expression of Buffy in the dopamine producing neurons resulted in flies with increased climbing ability and enhanced survival, while the inhibition of Buffy in the dopaminergic neurons reduced climbing ability over time prematurely, similar to the phenotype observed in the α-synuclein-induced Drosophila model of PD. Subsequently, the expression of Buffy was altered in the α-synuclein-induced Drosophila model of PD. Analysis revealed that Buffy acted to rescue the associated loss of locomotor ability observed in the α-synuclein-induced model of PD, while Buffy RNA interference resulted in an enhanced α-synuclein-induced loss of climbing ability. In complementary experiments the overexpression of Buffy in the developing eye suppressed the mild rough eye phenotype that results from Gal4 expression and from α-synuclein expression. When Buffy is inhibited the roughened eye phenotype is enhanced.ConclusionsThe inhibition of Buffy in DA neurons produces a novel model of PD in Drosophila. The directed expression of Buffy in DA neurons provide protection and counteracts the α-synuclein-induced Parkinson disease-like phenotypes. Taken all together this demonstrates a role for Buffy, a Bcl-2 pro-cell survival gene, in neuroprotection.
Highlights
In contrast to the complexity found in mammals, only two B cell lymphoma 2 (Bcl-2) family genes have been found in Drosophila melanogaster including the pro-cell survival, human Bok-related orthologue, Buffy
First we examine the effects of increasing and decreasing Buffy activity in dopaminergic neurons (DA) neurons and, secondly, we investigate the potential suppression of the α-synuclein-induced Parkinson disease (PD) phenotypes by the overexpression of the pro-survival Bcl-2 homologue Buffy
The Eukaryotic Linear Motif (ELM) resource search for functional sites indicates the presence of a monopartite variant of a basically charged NLS between amino acids 101 and 106
Summary
In contrast to the complexity found in mammals, only two Bcl-2 family genes have been found in Drosophila melanogaster including the pro-cell survival, human Bok-related orthologue, Buffy. The directed expression of α-synuclein, the first gene identified to contribute to inherited forms of Parkinson disease (PD), in the dopaminergic neurons (DA) of flies has provided a robust and well-studied Drosophila model of PD complete with the loss of neurons and accompanying motor defects. The first Drosophila model of PD utilized a human α-synuclein transgene to induce the PD-like symptoms [12] The success of this model is its ability to recapitulate features of human PD such as (1) age-dependent loss in locomotor function (2) LBlike inclusions and (3) age-dependent loss of DA neurons; and has found wide use for studying the molecular basis of α-synuclein-induced neurodegeneration [12,13,14,15,16,17,18,19]. The association of α-synuclein with components of the mitochondria is thought to lead to oxidative stress, apoptosis, autophagy and the eventual neurodegeneration
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