Metabolic and neurobehavioral disturbances induced by purine recycling deficiency in Drosophila
Céline Petitgas,
Laurent Seugnet,
Amina Dulac,
Giorgio Matassi,
Ali Mteyrek,
Rebecca Fima,
Marion Strehaiano,
Joana Dagorret,
Baya Chérif-Zahar,
Sandrine Marie,
Irène Ceballos-Picot,
Serge Birman
Affiliations
Céline Petitgas
Genes Circuits Rhythms and Neuropathology, Brain Plasticity Unit, CNRS, ESPCI Paris, PSL Research University, Paris, France; Metabolomic and Proteomic Biochemistry Laboratory, Necker-Enfants Malades Hospital and Paris Cité University, Paris, France
Dipartimento di Scienze Agroalimentari, Ambientali e Animali, University of Udine, Udine, Italy; UMR “Ecology and Dynamics of Anthropogenic Systems” (EDYSAN), CNRS, Université de Picardie Jules Verne, Amiens, France
Ali Mteyrek
Genes Circuits Rhythms and Neuropathology, Brain Plasticity Unit, CNRS, ESPCI Paris, PSL Research University, Paris, France
Rebecca Fima
Genes Circuits Rhythms and Neuropathology, Brain Plasticity Unit, CNRS, ESPCI Paris, PSL Research University, Paris, France
Marion Strehaiano
Genes Circuits Rhythms and Neuropathology, Brain Plasticity Unit, CNRS, ESPCI Paris, PSL Research University, Paris, France
Joana Dagorret
Genes Circuits Rhythms and Neuropathology, Brain Plasticity Unit, CNRS, ESPCI Paris, PSL Research University, Paris, France
Baya Chérif-Zahar
Genes Circuits Rhythms and Neuropathology, Brain Plasticity Unit, CNRS, ESPCI Paris, PSL Research University, Paris, France
Sandrine Marie
Laboratory of Metabolic Diseases, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium
Irène Ceballos-Picot
Metabolomic and Proteomic Biochemistry Laboratory, Necker-Enfants Malades Hospital and Paris Cité University, Paris, France
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 N6-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 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.
