SIRT6 and Neurodegenerative Disease: A New Therapeutic Target
Tryptophan, frequently enough associated with sleep, plays a crucial role in brain health, contributing to protein synthesis, energy production (NAD+), and the creation of vital neurotransmitters like serotonin and melatonin. Disruptions in tryptophan metabolism are increasingly linked to aging, neurodegenerative diseases, and psychiatric disorders, leading to mood disturbances, impaired learning, and sleep problems. Recent research has pinpointed a key regulator of this process: the Sirtuin 6 (SIRT6) protein.
The Role of SIRT6 in Brain Chemistry
Researchers at Ben-Gurion University of the Negev, led by Prof. Debra Toiber, have discovered that declining levels of SIRT6 are a major driver of metabolic imbalances in the brain. Their work, published in Nature Communications, demonstrates that SIRT6 controls gene expression related to tryptophan metabolism (including TDO2 and AANAT). When SIRT6 levels decrease, this control is lost, leading to a shift in tryptophan processing.
Specifically,tryptophan is increasingly diverted towards the kynurenic pathway,which produces neurotoxic compounds. Together, the production of protective neurotransmitters like serotonin and melatonin declines. This imbalance contributes to the progression of neurological issues.
Experimental Evidence
The research team conducted experiments using cells, Drosophila (fruit flies), and mouse models to validate their findings. In a SIRT6 knockout fly model, blocking the enzyme TDO2 significantly improved movement problems and reduced the formation of vacuoles – indicators of brain tissue damage. This suggests that targeting TDO2 could offer a therapeutic avenue for mitigating the effects of SIRT6 loss.
Therapeutic implications and Future Research
prof. Toiber emphasizes that their research identifies SIRT6 as a critical upstream drug target for combating neurodegenerative pathology. The finding that the damage caused by SIRT6 loss is perhaps reversible offers a promising window for therapeutic intervention. Further research is needed to develop strategies to boost SIRT6 levels or counteract the effects of its decline.
Research Support
This study was supported by several organizations, including:
- European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No 849029)
- David and Inez Myers foundation
- Israeli Ministry of Science and Technology (MOST)
- High-tech, Bio-tech and negev fellowships of Kreitman School of Advanced Research of Ben-Gurion University
- The Israel Science Foundation (Grant no. 422/23)
- Russian Science Foundation (grant number 25-71-20017) – for RNA-seq data analysis
key Takeaways
- Declining SIRT6 levels disrupt tryptophan metabolism in the brain.
- this disruption leads to increased production of neurotoxic compounds and decreased production of protective neurotransmitters.
- Blocking the TDO2 enzyme can reverse some of the damage caused by SIRT6 loss.
- SIRT6 represents a promising therapeutic target for neurodegenerative diseases.
Publication Date: 2026/01/17 02:16:37
