Study of the pathogenic mechanisms of Lesch-Nyhan disease in relation to the dopaminergic system in a model organism, Drosophila melanogaster ; Etude des mécanismes pathogéniques de la maladie de Lesch-Nyhan en relation avec le système dopaminergique chez un organisme modèle, Drosophila melanogaster

Adenine phosphoribosyltransferase (APRT) and hypoxanthine-guanine phosphoribosyltransferase (HGPRT) are two major enzymes involved in purine recycling in mammals, an essential metabolic pathway that allows the recovery of free purine bases derived from diet or the degradation of nucleotides. The purine salvage pathway is indeed less energy costly than de novo purine synthesis and its dysfunction induces various pathologies. In particular, inherited mutations suppressing HGPRT enzyme activity are associated with Lesch-Nyhan disease (LND), a rare X-linked metabolic and neurophysiological disorder in children, characterized by hyperuricemia and severe neurobehavioural disturbances such as dystonia, spasticity and compulsive self-injury. Studies have shown that LND patients have markedly reduced dopamine levels specifically in the basal ganglia, but the mechanisms linking the lack of HPRT activity and dopaminergic neurotransmission have not been elucidated to date. In this thesis work, we have been studying the relation between purine metabolism and the dopaminergic system in a model organism, Drosophila, with the aim to find new clues about the mechanisms involved in LND. No HGPRT homologue is present in the Drosophila genome, which suggests that the APRT homologue, named Aprt, is the only purine-recycling enzyme in this organism. Our work shows that Aprt-deficient flies have defects partly comparable to those associated with HGPRT deficiency in humans, notably an increase in uric acid levels, as well as alterations in dopaminergic markers and neurobehavioural defects. Conversely, genetic disruptions of the dopaminergic system decrease the expression and activity level of Aprt. Our results therefore confirm the conservation of a physiological link between purine recycling and the dopaminergic system in Drosophila, and further indicate that this regulation requires adenosinergic signaling. This new model could therefore prove valuable to find new therapeutic targets and possibly improve the cure of this dramatic ...