Metabolic and neurobehavioral disturbances induced by purine recycling deficiency inDrosophila

Abstract

Lesch-Nyhan disease (LND) is a rare genetic disorder induced by deficiency in hypoxanthine-guanine phosphoribosyltransferase (HGPRT), an enzyme of the purine salvage pathway. This leads in early age to hyperuricemia and severe neurobehavioral disturbances, including dystonia, spasticity and compulsive self-injury. To date, no treatment is available for these neurological symptoms and no animal model recapitulates all the defects observed in LND patients. Here we studied LND-related mechanisms in the fruit flyDrosophila melanogaster. We confirmed that no HGPRT activity is expressed in this organism, where the only purine-recycling enzyme is adenine phosphoribosyltransferase (Aprt). This enzyme is also present in humans but its deficiency does not trigger neurological defects. In contrast, we observed thatDrosophilaAprtmutants showed both metabolic and neurobehavioral disturbances, including increased uric acid levels, locomotor reactivity impairments, sleep alterations, seizure-like behavior, reduced lifespan, and reduction of adenosine signaling and content. Locomotor defects could be rescued by neuronalAprtre-expression in mutant context and reproduced by knocking downAprtselectively in the protocerebral anterior medial (PAM) clusters of dopaminergic neurons, the mushroom bodies and glia subsets. Ingestion of allopurinol normalized uric acid levels inAprtmutants but not their neurological defects, as is the case in LND patients, whereas feeding adenosine orN6-methyladenosine during development fully rescued the epileptic behavior. Intriguingly, pan-neuronal expression of an LND-associated mutant form of human HGPRT (I42T), but not the wild-type enzyme, resulted in early locomotor defects and seizure in flies, similar toAprtdeficiency. Overall, this shows thatDrosophilacan be used as a new model in different ways to better understand LND and seek a cure for this dramatic disease.