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 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 elevates the concentration of neurotoxic metabolites at the expense of serotonin and melatonin production. Such neurotoxic metabolites are AhR ligands. Downstream, SIRT6 influences aryl-hydrocarbon receptor (AhR) function by altering its expression, recruitment to chromatin, and by affecting its ligands from tryptophan metabolites. However, by redirecting tryptophan through TDO2 inhibition in our new SIRT6-KO Drosophila model, the impairments in neuromotor behavior and parameters of neurodegeneration could be significantly reversed.