Neuronal death in Drosophila triggered by GAL4 accumulation.
The GAL4/UAS system has been extensively employed in Drosophila to control gene expression in defined spatial patterns. More recently this system has been successfully applied to express genes involved in neurodegeneration to model various diseases in the fruit fly. We used transgenic lines expressing different levels of GAL4 in a particular subset of neurons involved in the control of rhythmic behaviour, so that its impact on neuronal physiology would result in altered locomotor activity, which could be readily assessed. We observed a striking correlation between gal4 dosage and behavioural defects associated with apoptotic neuronal loss in the specific GAL4-expressing neurons. Increased gal4 dosage correlated with accumulation of insoluble GAL4, suggesting that the cascade of events leading to apoptosis might be triggered by protein deposits of either GAL4 or protein intermediates. Behavioural defects were rescued by expression of hsp70, a classic chaperone that also interferes with cell death pathways. In agreement with the latter, the viral caspase inhibitor p35 also rescued GAL4-induced behavioural defects. Our observations demonstrate the intrinsic effects of GAL4 deregulation on neuronal viability and suggest that an excess of GAL4 might enhance neuronal deficits observed in models of neurodegeneration.
Rezával
Carolina
C
Laboratorio de Genética del Comportamiento, Fundación Instituto Leloir, Av. Patricias Argentinas 435, Buenos Aires 1405, Argentina.
Werbajh
Santiago
S
Ceriani
María Fernanda
MF
D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D004268:DNA-Binding Proteins; D004330:Drosophila; D018628:Gene Dosage / Q000502:physiology; D005786:Gene Expression Regulation; D020287:In Situ Nick-End Labeling; D007814:Larva / Q000502:physiology; D008297:Male; D008855:Microscopy, Electron, Scanning; D009043:Motor Activity / Q000502:physiology; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D009474:Neurons / Q000473:pathology* / Q000502:physiology; D010641:Phenotype; D017956:Photoreceptor Cells, Invertebrate / Q000502:physiology / Q000648:ultrastructure; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D019076:Transgenes / Q000502:physiology*
D004268:DNA-Binding Proteins; C052130:GAL4 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors