Abstract
BackgroundThe identification of a DNA variant in pyridoxal kinase (Pdxk) associated with increased risk to Parkinson disease (PD) gene led us to study the inhibition of this gene in the Dopa decarboxylase (Ddc)-expressing neurons of the well-studied model organism Drosophila melanogaster. The multitude of biological functions attributable to the vitamers catalysed by this kinase reveal an overabundance of possible links to PD, that include dopamine synthesis, antioxidant activity and mitochondrial function. Drosophila possesses a single homologue of Pdxk and we used RNA interference to inhibit the activity of this kinase in the Ddc-Gal4-expressing neurons. We further investigated any association between this enhanced disease risk gene with the established PD model induced by expression of α-synuclein in the same neurons. We relied on the pro-survival functions of Buffy, an anti-apoptotic Bcl-2 homologue, to rescue the Pdxk-induced phenotypes.ResultsTo drive the expression of Pdxk RNA interference in DA neurons of Drosophila, we used Ddc-Gal4 which drives expression in both dopaminergic and serotonergic neurons, to result in decreased longevity and compromised climbing ability, phenotypes that are strongly associated with Drosophila models of PD. The inhibition of Pdxk in the α-synuclein-induced Drosophila model of PD did not alter longevity and climbing ability of these flies. It has been previously shown that deficiency in vitamers lead to mitochondrial dysfunction and neuronal decay, therefore, co-expression of Pdxk-RNAi with the sole pro-survival Bcl-2 homologue Buffy in the Ddc-Gal4-expressing neurons, resulted in increased survival and a restored climbing ability. In a similar manner, when we inhibited Pdxk in the developing eye using GMR-Gal4, we found that there was a decrease in the number of ommatidia and the disruption of the ommatidial array was more pronounced. When Pdxk was inhibited with the α-synuclein-induced developmental eye defects, the eye phenotypes were unaltered. Interestingly co-expression with Buffy restored ommatidia number and decreased the severity of disruption of the ommatidial array.ConclusionsThough Pdxk is not a confirmed Parkinson disease gene, the inhibition of this kinase recapitulated the PD-like symptoms of decreased lifespan and loss of locomotor function, possibly producing a new model of PD.
Highlights
The identification of a DNA variant in pyridoxal kinase (Pdxk) associated with increased risk to Parkinson disease (PD) gene led us to study the inhibition of this gene in the Dopa decarboxylase (Ddc)-expressing neurons of the well-studied model organism Drosophila melanogaster
Pdxk is evolutionarily conserved across diverse species The bioinformatic analysis of protein sequences encoded by the human, mouse, mosquito and fruit fly Pdxk gene revealed a highly conserved ribokinase/pyridoxal kinase domain (Fig. 1) as determined by National Center for Biotechnology Information (NCBI) Conserved Domain Database (CDD) [31] and Eukaryotic linear motif (ELM) resource [32]
The predicted Drosophila protein appears to be localised in the cytoplasm as predicted by MultiLoc2 [34], and to possess active sites and motifs that include a weak nuclear export signal (NES) as determined by NetNES [35], a nuclear localization signal (NLS) that was detected by cNLS Mapper [36], and a transmembrane (TM) domain as predicted by TMpred [37]
Summary
The identification of a DNA variant in pyridoxal kinase (Pdxk) associated with increased risk to Parkinson disease (PD) gene led us to study the inhibition of this gene in the Dopa decarboxylase (Ddc)-expressing neurons of the well-studied model organism Drosophila melanogaster. We further investigated any association between this enhanced disease risk gene with the established PD model induced by expression of α-synuclein in the same neurons. PD is characterized by the presence of neuronal inclusions composed of abnormal α-synuclein and generally referred to as Lewy-related pathology [2, 5]. This atypical protein accumulation is believed to lead to cellular toxicity and, eventually, the PD pathogenesis. The understanding and exploitation of the genetic basis of PD has revealed over 20 genes that are implicated in PD pathogenesis [8], and highlighted the complexity of this neurodegenerative disease
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