Drosophila cd Mutant of the Kynurenine Pathway as a Model for Dementia-Like Disorders. Ekatherina Nikitina, Yulia Dolgaya, Nadiya Utesheva, Elena Savvateeva-Popova. Dept Neurogenetics, Pavlov Inst Physiology, St Petersburg, Russian Federation.

   Neurodegenerative diseases, accompanied by cognitive disturbances, i.e gradual memory loss (dementia), are characterized by late onset, relentless progression, and finally death. Molecular-genetic studies of the human genome have emphasized the evolutionary conservation of homologous genes from different organisms. Drosophila mutants with phenotypes similar to neurodegenerative diseases accompanied by dementia might help to unravel the etiology of these polygenic disorders. A large number of neurodegenerative diseases are known to share a common pathological feature of abnormal brain deposits. It results from the alterations in the functioning of heat shock/chaperone machinery. Moreover, neurodegenerative disorders are characterized by altered content of the intermediates of the kynurenine pathway of trypthophan metabolism (KPTM). We developed Drosophila mutant model which reproduces main symptoms of neurodegenerative diseases. Mutant cardinal (cd, excess of 3-hydroxykynurenine, 3-HOK, the generator of oxidative stress) can serve as model for dementia since it is characterized by age-dependent memory loss, synaptic pathology, apoptosis under heat shock. Here, we tested the effects of heat shock (HS) on the main disease manifestations - impairments in learning/memory and HSP70 intracellular localization. For this, we used a 30-min HS given at the stage of formation of the central complex implicated in learning and memory. Having no effect on wild type flies (CS), HS in cd mutants lead to a drastic 4-fold and 10-fold decrease in long-term memory retention tested 2 and 8 days after training. Using confocal microscopy we demonstrated a decrease in anti- HSP70 staining in cd cells in comparison to wild type under normal and stress conditions. Without heat shock HSP70 was determined on nuclear surface both in cd and CS. In both stocks HS treatment resulted in HSP70 relocation into the nuclei. Found differences can result from an accumulation of 3-HOK in cd mutant. Therefore, the cd mutant may be regarded as an appropriate model for dementia-like disorders.