cd¹ 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 (cd¹) 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 cd¹ mutation, its molecular nature remained obscure. Using next generation sequencing, we have shown that the cd gene in cd¹ carries a long deletion leading to PHS active site destruction. Contrary to the wild type Canton-S (CS), cd¹ 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 cd¹ 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 cd¹ provokes drastic LTM impairments and DAN alterations.