The directed expression of genes associated with apoptosis and autophagy, two very important cellular processes, under the direction of the Ddc-Gal4 transgene in dopaminergic (DA) neurons has distinct effects upon behavioural attributes of Drosophila melanogaster.
Buffy, the single pro-cell survival member of the Bcl-2 family, extends lifespan and improves locomotor ability when overexpressed in the dopaminergic neurons. Furthermore, we showed that Buffy overexpression was sufficient to restore lifespan and age-dependent loss in locomotor ability in the robust α-synuclein-induced Parkinson disease model in Drosophila. In addition, the overexpression of the pro-apoptotic Bcl-2 homologue debcl leads to a greatly shortened lifespan and severely reduced climbing ability, phenotypes that are strongly associated with Parkinson disease (PD), and may as well provide a novel model for PD.
Subsequently, we have been able to demonstrate that the directed inhibition of two autophagic genes; Atg6 and Pi3K59F; apoptotic genes; Bax inhibitor-1 (BI-1), Lifeguard (LFG), Growth hormone-inducible transmembrane protein (GHITM), High temperature requirement A2 (HtrA2); and multifunctional genes; pyridoxal kinase (Pdxk) and voltage-dependent anion channel (VDAC/porin) results in shortened lifespans and defective climbing abilities. We show that the overexpression of the anti-apoptotic Bcl-2 homologue Buffy in DA neurons when co-expressed with the apoptotic and autophagic genes suppresses the PD-like phenotypes described above.
The loss in function of a number of autophagic and apoptotic genes in the dopaminergic neurons of Drosophila leads to shortened lifespans and the progressive loss of locomotor abilities and Buffy is able to improve the “healthspan” of these flies.
Funded by a School of Graduate Studies Fellowship and by an NSERC Discovery Grant.