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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., Competing Interests: CP, LS, AD, GM, AM, RF, MS, JD, BC, SM, IC, SB No competing interests declared, (© 2023, Petitgas et al.)

Sleep disorders are commonplace in our modern societies. Specialized hospital departments are generally overloaded, and sleep assessment is an expensive process in terms of equipment, human resources, and time. Biomarkers would usefully complement current measures in the screening and follow-up of sleep disorders and their daytime repercussions. Among salivary markers, a growing body of literature suggests that salivary α-amylase (sAA) may be a cross-species marker of sleep debt. However, there is no consensus as to the direction of variation in sAA with sleep disorders. Herein, after describing the mechanisms of sAA secretion and its relationship with stress, studies assessing the relationship between sAA and sleep parameters are reviewed. Finally, the influence of confounding factors is discussed, along with methodological considerations, to better understand the fluctuations in sAA and facilitate future studies in the field., Competing Interests: Declaration of competing interest The authors do not have any conflicts of interest to disclose., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The Pallidin protein is a central subunit of a multimeric complex called biogenesis of lysosome-related organelles complex 1 (BLOC1) that regulates specific endosomal functions and has been linked to schizophrenia. We show here that downregulation of Pallidin and other members of BLOC1 in the surface glia, the Drosophila equivalent of the blood-brain barrier, reduces and delays nighttime sleep in a circadian-clock-dependent manner. In agreement with BLOC1 involvement in amino acid transport, downregulation of the large neutral amino acid transporter 1 (LAT1)-like transporters JhI-21 and mnd, as well as of TOR (target of rapamycin) amino acid signaling, phenocopy Pallidin knockdown. Furthermore, supplementing food with leucine normalizes the sleep/wake phenotypes of Pallidin downregulation, and we identify a role for Pallidin in the subcellular trafficking of JhI-21. Finally, we provide evidence that Pallidin in surface glia is required for GABAergic neuronal activity. These data identify a BLOC1 function linking essential amino acid availability and GABAergic sleep/wake regulation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Sleepiness is associated with decreased cognitive abilities and remains one of the main causes of fatal road accidents. The tools currently available to assess sleepiness, such as questionnaires, are subject to intra- and inter-individual variability, while multiple sleep latency tests are only feasible in few sleep laboratories. The main objective of this study was to explore new potential markers (neurocognitive, biological) to objectively assess sleepiness in drivers., Methods: A total of 186 drivers (median age 44 years, range 20-74 years, 73% men, 14% obese) were included during a break at a highway service area, in the morning, while on the road for vacation. Questionnaires on sleepiness and sleep characteristics (habitual and on the night before travel), the Bron-Lyon Attention Stability Test (BLAST), and two salivary samples (α-amylase and oxalate) were collected. Associations between measures of sleepiness [Epworth Sleepiness Scale (ESS), and Stanford Sleepiness Scale (SSS)], sleep characteristics, neurocognitive, and biological markers were tested using regression models adjusted for confounding factors., Results: The night before travel, 83% of the drivers reduced their sleep time and 30% slept 5 h or less. The higher the number of miles to be traveled, the higher the decrease, and the shorter the sleep time. The night before travel, 18 and 24% of the drivers complained of poor sleep quality and difficulty falling asleep. The sleep characteristics on the night before travel were associated with the habitual sleep characteristics. At the time of the test, 47% of the drivers scored pathologically on the SSS. Poor sleep quality and difficulty falling asleep the night before travel were associated with increased sleepiness as assessed by the SSS and decreased attentional ability as assessed by the BLAST. No association between salivary markers and acute sleepiness was observed., Conclusions: The sleep characteristics of the night before travel were associated with sleepiness and attentional performance. The SSS and the BLAST could be used by individual drivers in a self-evaluation context. Biological markers showed a high variability and limited association with sleep parameters across subjects, emphasizing the need for within-subject designs to assess their usefulness., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Thieux, Guyon, Herbillon, Merle, Lachaux, Plancoulaine, Seugnet and Franco.)