Abstract
AbstractAdenine phosphoribosyltransferase (APRT) and hypoxanthine-guanine phosphoribosyltransferase (HGPRT) are two structurally related enzymes involved in purine recycling in humans. Inherited mutations that suppress HGPRT activity are associated with Lesch-Nyhan disease (LND), a rare X-linked metabolic and neurological disorder in children, characterized by hyperuricemia, dystonia and compulsive self-injury. To date, no treatment is available for these neurological defects and no animal model recapitulates all symptoms of LND patients. Here we studied LND-related mechanisms in the fruit fly. By combining enzymatic assays and phylogenetic analysis, we confirm that no HGPRT activity is expressed inDrosophila melanogaster, making the APRT homologue (Aprt) the only purine-recycling enzyme in this organism. Whereas APRT deficiency does not trigger neurological defects in humans, we observed thatDrosophila Aprtmutants show both metabolic and neurobehavioral disturbances, including increased uric acid levels, locomotor impairments, sleep alterations, seizure-like behavior, reduced lifespan, and reduction of adenosine signaling and content. Locomotor defects could be rescued by Aprt re-expression in neurons and reproduced by knocking downAprtselectively in the protocerebral anterior medial (PAM) dopaminergic neurons, the mushroom bodies or glia subsets. Ingestion of allopurinol rescued uric acid levels inAprt-deficient mutants but not neurological defects, as is the case in LND patients, while feeding adenosine orN6-methyladenosine (m6A) 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, our results suggest thatDrosophilacould be used in different ways to better understand LND and seek a cure for this dramatic disease.
Publisher
Cold Spring Harbor Laboratory