The amino acid tryptophan, often recognized for its association with promoting sleep, plays a far more intricate and crucial role within the complex biochemical landscape of the human brain, influencing not only restful slumber but also fundamental aspects of cognitive function and emotional well-being. This essential building block is a precursor to vital compounds that underpin protein synthesis, drive cellular energy production through pathways like NAD+ generation, and are indispensable for the creation of key neurotransmitters such as serotonin, which modulates mood, and melatonin, which orchestrates circadian rhythms. The collective impact of these tryptophan-derived molecules is profound, supporting a healthy equilibrium in mood regulation, facilitating effective learning processes, and ensuring the establishment and maintenance of robust sleep cycles.
However, as the brain navigates the processes of aging or succumbs to the insidious progression of neurological diseases, this finely tuned metabolic system can begin to falter. A growing body of scientific evidence has consistently highlighted disruptions in the way aging brains process tryptophan, with these aberrant patterns becoming even more pronounced and detrimental in the context of neurodegenerative conditions and psychiatric disorders. Such metabolic shifts are invariably linked to a cascade of negative neurological consequences, including a decline in mood, a demonstrable impairment in cognitive abilities such as learning and memory, and significant disturbances in sleep architecture. Until recently, the precise trigger that initiates this critical redirection of tryptophan metabolism within the brain remained an elusive puzzle for researchers.
A groundbreaking investigation spearheaded by Professor Debra Toiber and her dedicated research team at Ben-Gurion University of the Negev has now illuminated a compelling biological explanation for this metabolic imbalance, pinpointing a specific protein as the pivotal orchestrator. Their extensive work has identified the decline of Sirtuin 6 (SIRT6), a protein intrinsically linked to cellular longevity and metabolic regulation, as the primary causal agent responsible for the observed shift in tryptophan utilization.
Through a series of meticulously designed experiments utilizing a range of model systems – including in vitro cell cultures, the fruit fly Drosophila, and mammalian mouse models – the researchers were able to demonstrate SIRT6’s active and critical function in governing gene expression. Specifically, SIRT6 exerts control over genes involved in tryptophan metabolism, such as TDO2 (tryptophan 2,3-dioxygenase) and AANAT (arylalkylamine N-acetyltransferase). The findings revealed that a reduction in SIRT6 levels leads to a diminished capacity for this regulatory control. Consequently, tryptophan is increasingly shunted down the kynurenine pathway, a metabolic route that, under these conditions, yields compounds with neurotoxic potential. Simultaneously, the synthesis of crucial neuroprotective neurotransmitters, including serotonin and melatonin, experiences a significant decline, further exacerbating the detrimental effects on brain health.
The profound implications of these discoveries have been formally documented and published in the esteemed scientific journal Nature Communications, providing a robust foundation for further research and therapeutic development. Crucially, the research team’s investigation extended beyond merely identifying the problem; they also uncovered compelling evidence suggesting that the neurological damage resulting from this metabolic derangement may not be an irreversible state. In experiments involving a SIRT6 knockout fly model, a genetic modification that effectively eliminates SIRT6 function, the researchers observed a remarkable reversal of negative effects. By pharmacologically inhibiting the TDO2 enzyme, a key player in the kynurenine pathway, they witnessed substantial improvements in motor deficits and a significant reduction in the formation of vacuoles. These vacuoles are cellular hallmarks indicative of brain tissue damage, and their decrease suggests a potential for recovery and restoration of neural integrity.
Professor Toiber articulated the significance of these findings, stating, "Our research positions SIRT6 as a critical, upstream drug target for combating neurodegenerative pathology." This declaration underscores the potential of targeting SIRT6 not just as a means to understand disease mechanisms, but as a viable strategy for developing novel therapeutic interventions aimed at halting or even reversing the progression of debilitating neurological conditions. The identification of SIRT6 as a master regulator opens a new avenue for pharmaceutical development, offering hope for conditions where current treatment options are limited.
The comprehensive study involved a multidisciplinary collaboration of researchers, including Shai Kaluski-Kopatch, Daniel Stein, Alfredo Garcia Venzor, Ana Margarida Ferreira Campos, Melanie Planque, Bareket Goldstein, Estefanía De Allende-Becerra, Dmitrii Smirnov, Adam Zaretsky, Dr. Ekaterina Eremenko-Sgibnev, Miguel Portillo, Monica Einav, Alena Bruce Krejci, Uri Abdu, Ekaterina Khrameeva, Daniel Gitler, and Sarah-Maria Fendt. This collaborative effort highlights the complex and multifaceted nature of modern scientific inquiry.
The groundbreaking research was generously supported by several prestigious funding bodies, underscoring the global recognition of its potential impact. Primary funding was provided by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program, under grant agreement No 849029. Additional support was extended by the David and Inez Myers Foundation, the Israeli Ministry of Science and Technology (MOST), and through the High-tech, Bio-tech, and Negev fellowships offered by the Kreitman School of Advanced Research at Ben-Gurion University. The Israel Science Foundation also contributed significantly through grant no. 422/23. Furthermore, the sophisticated analysis of RNA-seq data, a crucial component of the study, received dedicated support from the Russian Science Foundation under grant number 25-71-20017. This array of international and national funding demonstrates a shared commitment to advancing our understanding of brain health and developing innovative solutions for neurological disorders.
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