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Abstract

Background. Bax Inhibitor-1 (BI-1), an integral transmembrane protein, acts as a suppressor of Bax-induced apoptosis through regulation of endoplasmic reticulum (ER) stress-induced cell death. The gene is highly conserved being found in a diverse range of organisms that include yeast, Arabidopsis, Drosophila, mouse and humans. BI-1 is implicated in the regulation of calcium levels, reactive oxygen species, apoptosis, autophagy and ER stress signalling pathways. We inhibited the cytoprotective BI-1 in the dopa decarboxylase (Ddc) expressing neurons and in the developing eye of Drosophila melanogaster to investigate its neuroprotective functions. Methods. We assessed the longevity and locomotor ability of flies in response to altered BI-1 expression in the Ddc-Gal4-expressing neurons where we exploited two RNAi transgenic fly lines. A control that expressed the benign lacZ responding transgene was used to compare against the RNAi transgenic flies. In addition, we compared the effect of the loss of BI-1 expression in the developing eye, through biometric analysis of the number of ommatidia and extent of disruption of the ommatidial arrays. Finally, Buffy and α-synuclein were co-expressed to evaluate the potential for interactions. Results. The inhibition of BI-1 in these neurons resulted in a shortened lifespan and precocious loss of locomotor ability. The co-expression of Buffy, the sole anti-apoptotic Bcl-2 homologue in Drosophila, with BI-1-RNAi resulted in suppression of the reduced lifespan and impaired climbing ability. Expression of human αsynuclein in Drosophila dopaminergic neurons results in age-dependent loss in climbing ability. We exploited this neurotoxic system to investigate possible BI-1 neuroprotective function. The co-expression of α-synuclein with BI-1-RNAi results in decreased survival coupled with an impaired climbing ability. In supportive experiments, we employed the neuron-rich Drosophila compound eye to investigate subtle phenotypes that result from altered gene expression. The inhibition of BI-1 in the Drosophila developing eye under the direction of the GMR-Gal4 transgene results in reduced ommatidia number and increased disruption of the ommatidial array. Similarly, the co-expression of BI-1-RNAi with Buffy results in the suppression of the eye phenotypes. The expression of α-synuclein along with