Hui Li Defense Thesis : Sleep-wake regulation by Pallidin via the brain-circulation interfaces

Hui Li (WAKING CRNL) defense thesis, supervised by Laurent Seugnet (WAKING CRNL), will take place on Thursday, June 23th at 2 pm in the Neurocampus amphitheater. The presentation will be in English. The jury members are: Véronique Fabre, François Rouyer, Anne Didier, Armelle Rancillac, and Serge Birman.                         

Title: Sleep-wake regulation by Pallidin via the brain-circulation interfaces.

Abstract

Sleep disorders are gradually gaining attention because of the serious consequences on our fitness and well-being. However, the metabolic and cellular processes linked to these disorders remain poorly understood. Starting from a transcriptomic analysis of narcoleptic mice performed in our laboratory, the expression of the gene pallidin was found to be strongly upregulated in mice with defective histaminergic transmission, suggesting a link between the cellular and molecular mechanisms controlled by the pallidin gene and sleep/wake regulation. To investigate this question, I used a genetic knockdown strategy in Drosophila and demonstrated that down-regulation of pallidin in the surface glia (SG), the Drosophila equivalent of the blood brain barrier, is sufficient to reduce, fragment and delay nighttime sleep at the adult stage. In addition, I found that pallidin is required for normal sleep regulation in both subtypes of surface glia, subperineurial (SPG) and perineurial (PG). Pallidin codes for a subunit of the BLOC-1 complex that regulates the biogenesis of lysosome-related organelles and I obtained evidence that other subunits of the BLOC-1 complex are involved in this pallidin-dependent sleep regulation. Interestingly, in agreement with Pallidin’s involvement in amino acid transport suggested by the literature, down-regulation of the Large neutral Amino acid Transporter 1 (LAT-1)-like transporters JhI-21 and minidiscs, as well as the target of rapamycin (TOR) amino acid signaling, phenocopy the downregulation of pallidin. Additionally, although supplementation of food with tryptophan, leucine, and valine had an effect on the JhI-21 downregulation sleep phenotype, only leucine supplementation normalized the pallidin downregulation sleep phenotype. Furthermore, I found that Pallidin plays a role in the subcellular trafficking of JhI-21 in Drosophila surface glial cells. However, I did not detect any changes in LAT-1 subcellular localization in the brain endothelial cells of pallidin mutant mice. Finally, I provide evidence that pallidin function in surface glia is required for GABAergic neurons activation involved in promoting sleep. Taken together, these data identify a novel role for Pallidin and BLOC-1 that, through LAT-1-like transporters subcellular trafficking, modulates essential amino acid availability and GABAergic sleep/wake regulation.

Keywords: BLOC-1, Blood brain barrier, Large neutral Amino acid Transporter 1, Drosophila, glial cells, sleep/wake