Drosophila mutants of the kynurenine pathway as a model for ageing studies.

Abstract

A search for Drosophila mutants with phenotypes similar to human diseases might help to unravel evolutionary conserved genes implicated in polygenic human disorders. Among these are neurodegenerative diseases, characterized by a late onset disturbance of memory, structural brain impairments and altered content of the intermediates of the kynurenine pathway. The ratio between kynurenate (KYNA) and 3-hydroxykynurenine (3-HOK) in the brain is a critical determinant of neuronal viability. Therefore, the Drosophila mutants cinnabar (KYNA excess) and cardinal (3-HOK excess) allow an evaluation of the specific roles of these metabolites which present in physiologic concentrations and mimic systemic administration. Previously we have demonstrated that the mutant cardinal can serve as a model for dementia and can help to unravel the earliest manifestations of brain dysfunction. Here we show that a state of the brain control of locomotor coordination characterized by the parameters of sound production in males results from the neuroprotective and neurotoxic effects of KYNA and 3-HOK accumulated in young and aged Drosophila mutants. The high instability of 1) cycle form and number in pulses; 2) of pulse amplitude and 3) rhythm in the courtship song of aged cardinal males are similar to the alterations in mutants with defective central complex of the brain. The cardinal mutants demonstrate apoptosis in the brain after stress treatment. This might reflect the misbalance in the content of excitatory amino acids' and the glycine site agonists revealed by HPLC-determination. The mutant cinnabar proved to be normal in respect of the parameters studied.