SIRT6 regulates Tryptophan catabolism preventing metabolite imbalance and neurodegeneration

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 elder and these ailments remain unknown. Our results from cellular, Drosophila melanogaster, and mouse models indicate that 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 our new SIRT6-KO Drosophila model, the impairments in neuromotor behavior and vacuolar formation a parameters of neurodegeneration could be significantly reversed. RNA was extracted from single head of 21 days old verging female w1118 / SIRT6 KO Drosophila fed with 100µM TDO2 inhibitor/ DMSO for 21 days.