In the brain, tryptophan byproducts are involved in the biosynthesis of proteins, energy-rich molecules (e.g., NAD+), and neurotransmitters (serotonin and melatonin). Impaired tryptophan catabolism, seen in aging, neurodegeneration and psychiatric diseases, affects mood, learning, and sleep; however, the reasons for those impairments in the elderly and in those suffering from these ailments remain unknown. Our results from cellular, Drosophila melanogaster, and mouse models indicate that Sirtuin 6 (SIRT6) regulates tryptophan catabolism by balancing its usage. Mechanistically, SIRT6 regulates tryptophan and sleep quality through changes in gene expression of key genes (e.g., TDO2, AANAT), which results in elevated concentration of neurotoxic metabolites from the kynurenic pathway at the expense of serotonin and melatonin production. Such neurotoxic metabolites can affect various processes in the brain. However, by redirecting tryptophan through TDO2 inhibition in a SIRT6 knockout D. melanogaster model, the impairments in neuromotor behavior and vacuolar formation - parameters of neurodegeneration - can be significantly reversed.

Center for Molecular and Cellular Biology Skolkovo Institute of Science and Technology Moscow Russia

Department of Life Sciences Faculty of Natural Sciences Ben Gurion University of the Negev Beer Sheva Israel

Department of Physiology and Cell Biology Faculty of Health Sciences Ben Gurion University of the Negev Beer Sheva Israel

Faculty of Science University of South Bohemia Ceske Budejovice Czechia

Laboratory of Cellular Metabolism and Metabolic Regulation Department of Oncology KU Leuven and Leuven Cancer Institute Leuven Belgium

Laboratory of Cellular Metabolism and Metabolic Regulation VIB KU Leuven Center for Cancer Biology Leuven Belgium

School of Brain Sciences and Cognition Ben Gurion University of the Negev Beer Sheva Israel

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