Inhibition of foxo and minibrain in Dopaminergic Neurons Can Model Aspects of Parkinson Disease in Drosophila melanogaster

Abstract

Symptoms of Parkinson Disease (PD), the second most common neurodegenerative disease, emergedue to degeneration of dopaminergic neurons. Recently, a genome wide study revealed a role for a foxo transcription factor in PD. In the model organism Drosophila melanogaster, we have attempted1) to inhibit the sole Drosophila homologue of foxo through the directed expression of astable inducible RNAi transgene and 2) to indirectly increase foxo transcription activity throughthe inhibition of the kinase minibrain (mnb), a foxo transcriptional inhibitor. To evaluate the lifetimeconsequences upon the flies, longevity assays and locomotion over time assays were conducted.The inhibition of foxo by foxo-RNAi decreases life span significantly when expressed underthe control of Tyrosine Hydroxylase-Gal4 (TH-Gal4). The targeted expression of mnb-RNAi, in thedopaminergic neurons, with an expected loss of suppression of foxo transcriptional activity, resultsin a significant loss of climbing ability. Thus alteration of foxo activity, both by RNA-inhibitionand by down-regulation of an inhibitor of foxo, minibrain, produces novel Drosophila models ofParkinson Disease.