A loss of Pdxk model of Parkinson disease in Drosophila can be suppressed by Buffy

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.

MicroRNA339 Targeting PDXK Improves Motor Dysfunction and Promotes Neurite Growth in the Remote Cortex Subjected to Spinal Cord Transection

“…Many neurotransmitters are synthesized by PDXK-dependent enzymes, including dopamine, noradrenaline, serotonin, and gamma-amino-butyric acid (GABA) (Dakshinamurti et al, 1990). Researchers agree that PDXK is associated with the pathogenesis of some nervous system diseases (NSDs) such as Down syndrome (Shin et al, 2004;Ramachandran et al, 2015), Parkinson's disease (Guella et al, 2010;Wider et al, 2010;M'Angale and Staveley, 2017), and seizures (Gachon et al, 2004;Galluzzi et al, 2013). However, the role of PDXK and its binding microRNA in SCI is largely unknown.…”

Sex-Specific Gene Expression in the Mouse Nucleus Accumbens Before and After Cocaine Exposure

“…The observed decrease in Htt expression in ovariectomized/placebo mice could have caused the observed decrease in the expression of these genes. Other potential Htt targets include Grin2d (NMDA receptor subunit 2D), Hap1 (Huntington associated protein 1), which binds Kalirin [46, 47], Fhl1 (four and a half LIM domains 1), Pdxk (pyridoxal kinase), a gene whose loss is associated with an increased risk of Parkinson disease [48], and Pnoc (prepronociceptin), a peptide precursor strongly implicated in neonatal abstinence syndrome [49]. Expression of each of these transcripts was reduced in ovariectomized/placebo vs cycling females (Fig.…”

The Therapeutic Potential of Vitamins B1, B3 and B6 in Charcot–Marie–Tooth Disease with the Compromised Status of Vitamin-Dependent Processes

“…The discrepancy in results is likely due to the different resolution of analytical procedures and/or cell-specific effects, themselves dependent on the tissue sampling. In a later work, inhibition of PDXK in a Drosophila model recapitulated symptoms of Parkinson's disease, such as decreased lifespan and loss of locomotor function [71]. Moreover, in a rat model of spinal cord injury, PDXK overexpression in the motor cortex improved neuronal growth and survival, as well as the locomotor function in the hindlimb.…”