cd(1) Mutation in Drosophila Affects Phenoxazinone Synthase Catalytic Site and Impairs Long-Term Memory

Being involved in development of Huntington’s, Parkinson’s and Alzheimer’s diseases, kynurenine pathway (KP) of tryptophan metabolism plays a significant role in modulation of neuropathology. Accumulation of a prooxidant 3-hydroxykynurenine (3-HOK) leads to oxidative stress and neuronal cell apoptosis. Drosophila mutant cardinal (cd(1)) with 3-HOK excess shows age-dependent neurodegeneration and short-term memory impairments, thereby presenting a model for senile dementia. Although cd gene for phenoxazinone synthase (PHS) catalyzing 3-HOK dimerization has been presumed to harbor the cd(1) mutation, its molecular nature remained obscure. Using next generation sequencing, we have shown that the cd gene in cd(1) carries a long deletion leading to PHS active site destruction. Contrary to the wild type Canton-S (CS), cd(1) males showed defective long-term memory (LTM) in conditioned courtship suppression paradigm (CCSP) at days 5–29 after eclosion. The number of dopaminergic neurons (DAN) regulating fly locomotor activity showed an age-dependent tendency to decrease in cd(1) relative to CS. Thus, in accordance with the concept “from the gene to behavior” proclaimed by S. Benzer, we have shown that the aberrant PHS sequence in cd(1) provokes drastic LTM impairments and DAN alterations.