Histone deacetylase SIRT6 regulates tryptophan catabolism and prevents metabolite imbalance associated with neurodegeneration
In the brain, tryptophan byproducts are involved in the biosynthesis of proteins, energy-rich molecules (e.g., NAD<sup>+</sup>), 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.
Authors
- Mélanie Planque (ORCID: https://orcid.org/0000-0001-7052-7084)
- Alena Krejčı́ (ORCID: https://orcid.org/0000-0001-7589-4035)
- Adam Zaretsky (ORCID: https://orcid.org/0000-0002-7475-1435)
- Dmitrii Smirnov (ORCID: https://orcid.org/0000-0002-5802-844X)
- Miguel Portillo
- Ana Margarida Ferreira Campos (ORCID: https://orcid.org/0000-0002-8832-7686)
- Daniel Stein (ORCID: https://orcid.org/0000-0003-4398-9421)
- Ekaterina E. Khrameeva (ORCID: https://orcid.org/0000-0001-6188-9139)
- Sarah‐Maria Fendt (ORCID: https://orcid.org/0000-0001-6018-9296)
- Uri Abdu (ORCID: https://orcid.org/0000-0003-1226-0750)
- Bareket Goldstein (ORCID: https://orcid.org/0009-0001-3021-9797)
- Monica Einav
- Daniel Gitler (ORCID: https://orcid.org/0000-0001-9544-3610)
- Alfredo García-Venzor (ORCID: https://orcid.org/0000-0002-4038-290X)
- Debra Toiber (ORCID: https://orcid.org/0000-0002-1465-0130)
- Estefanía De Allende-Becerra (ORCID: https://orcid.org/0009-0003-8055-8695)
- Ekaterina Eremenko
- Shai Kaluski-Kopatch (ORCID: https://orcid.org/0000-0002-3457-2299)
Institutions
- Ben-Gurion University of the Negev (IL)
- Skolkovo Institute of Science and Technology (RU)
- University of South Bohemia in České Budějovice (CZ)
- VIB-KU Leuven Center for Cancer Biology (BE)
- KU Leuven (BE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-04
- DOI
- https://doi.org/10.1038/s41467-025-67021-y
- Citations
- 2
- Primary Topic
- Sirtuins and Resveratrol in Medicine
- Type
- article
- Field-Weighted Citation Impact
- 2.45
Funders
- European Commission
- Ben-Gurion University of the Negev
- Russian Science Foundation
- National Institutes of Health