Metabolic and neurobehavioral disturbances induced by purine recycling deficiency in Drosophila

• Published in: eLife Vol. 12
• Main Authors: Petitgas, Céline, Seugnet, Laurent, Dulac, Amina, Matassi, Giorgio, Mteyrek, Ali, Fima, Rebecca, Strehaiano, Marion, Dagorret, Joana, Chérif-Zahar, Baya, Marie, Sandrine, Ceballos-Picot, Irène, Birman, Serge
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 03.05.2024; eLife Sciences Publications Ltd; eLife Sciences Publication
• Subjects: Adenine phosphoribosyltransferase; adenine phosphoribosyltransferase (APRT); adenosine signaling; Allopurinol; Amino acids; Analysis; Animal models; Animals; Behavior, Animal; Brain; Care and treatment; Cognitive science; Deficient mutant; Disease Models, Animal; Dopamine receptors; dopaminergic neurons; Drosophila; Drosophila melanogaster - genetics; Drosophila melanogaster - physiology; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Dystonia; Enzymes; Epilepsy; Fruit-flies; Gout; Hyperuricemia; Hypoxanthine; Hypoxanthine Phosphoribosyltransferase - deficiency; Hypoxanthine Phosphoribosyltransferase - genetics; Hypoxanthine Phosphoribosyltransferase - metabolism; hypoxanthine-guanine phosphoribosyltransferase (HGPRT); Insects; Lesch-Nyhan Syndrome - genetics; Lesch-Nyhan Syndrome - metabolism; Lesch–Nyhan disease; Life Sciences; Life span; Locomotion; Medical research; Medicine, Experimental; Metabolism; Mushroom bodies; Mutation; N6-methyladenosine; Nervous system diseases; Neuronal-glial interactions; Neurophysiology; Neuroscience; Phosphoribosyltransferase; Phylogenetics; Phylogeny; Proteins; purine salvage pathway; Purines - metabolism; Recycling; Scientific equipment and supplies industry; Seizures; Self-injury; Toxicity; Uric acid; France; United States; Massachusetts; adenine phosphoribosyltransferase (APRT); genetics; Lesch–Nyhan disease; neuroscience; dopaminergic neurons; hypoxanthine-guanine phosphoribosyltransferase (HGPRT); genomics; purine salvage pathway; D. melanogaster; adenosine signaling; Dopaminergic neurons; Adenosine signaling; Adenine phosphoribosyltransferase (APRT); Purine salvage pathway; Hypoxanthine-guanine phosphoribosyltransferase (HGPRT); Lesch-Nyhan disease
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.88510

Adenine 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 in Drosophila melanogaster , making the APRT homolog (Aprt) the only purine-recycling enzyme in this organism. Whereas APRT deficiency does not trigger neurological defects in humans, we observed that Drosophila Aprt mutants 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 down Aprt selectively in the protocerebral anterior medial (PAM) dopaminergic neurons, the mushroom bodies, or glia subsets. Ingestion of allopurinol rescued uric acid levels in Aprt -deficient mutants but not neurological defects, as is the case in LND patients, while feeding adenosine or N 6 -methyladenosine (m 6 A) 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 to Aprt deficiency. Overall, our results suggest that Drosophila could be used in different ways to better understand LND and seek a cure for this dramatic disease.