Research finds inhibiting TDO2 reverses neuromotor decline linked to tryptophan metabolism — Evidence Review
Published in Nature Communications, by researchers from Ben-Gurion University of the Negev
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Table of Contents
Scientists at Ben-Gurion University have identified how the loss of the SIRT6 protein in aging brains disrupts tryptophan metabolism, leading to neurotoxic effects and neurodegeneration. Most related studies broadly support these findings, showing that manipulating tryptophan metabolism pathways, especially via TDO2 inhibition, can influence neurodegenerative outcomes (1, 2, 3).
- Multiple studies in animal and cellular models demonstrate that TDO2 inhibition reduces neurodegeneration and improves motor function, aligning with the new study's findings that loss of SIRT6 increases TDO2-driven neurotoxicity (1, 2, 3).
- Existing research indicates that altered amino acid metabolism, including tryptophan pathways, contributes to neurodegeneration in aging and disease, supporting the importance of metabolic control in brain health (9).
- While most studies suggest therapeutic benefits for targeting TDO2 or related enzymes, some raise concerns about potential long-term effects of enzyme inhibition and emphasize the need for selective, well-tolerated interventions (3).
Study Overview and Key Findings
Age-related neurodegenerative diseases often involve disrupted metabolic pathways in the brain, but the underlying molecular triggers are not fully understood. This study addresses a significant knowledge gap by connecting the longevity-associated protein SIRT6 to the regulation of tryptophan metabolism—a pathway implicated in mood, cognition, and neurodegeneration. By using multiple model organisms, the research not only identifies SIRT6 as a central regulator but also demonstrates that the neurodegenerative effects of its loss can be therapeutically reversed, highlighting the translational potential of these findings.
| Property | Value |
|---|---|
| Study Year | 2025 |
| Organization | Ben-Gurion University of the Negev |
| Journal Name | Nature Communications |
| Authors | Shai Kaluski-Kopatch, Daniel Stein, Alfredo Garcia Venzor, Ana Margarida Ferreira Campos, Melanie Planque, Bareket Goldstein, Estefanía De Allende-Becerra, Dmitrii Smirnov, Adam Zaretsky, Ekaterina Eremenko, Miguel Portillo, Monica Einav, Alena Bruce Krejci, Uri Abdu, Ekaterina Khrameeva, Daniel Gitler, Sarah-Maria Fendt, Debra Toiber |
| Population | Drosophila, mice, and cell models |
| Methods | Animal Study |
| Outcome | Tryptophan metabolism and neurodegeneration |
| Results | Inhibiting TDO2 reversed neuromotor decline in flies. |
Literature Review: Related Studies
To place these findings in context, we searched the Consensus database, which contains over 200 million research papers. The following queries were used to identify relevant studies:
- TDO2 inhibition neuromotor decline
- aging brain amino acid toxicity
- neuroprotection mechanisms in aging flies
| Topic | Key Findings |
|---|---|
| How does TDO2 inhibition impact neurodegeneration and neuromotor decline? | - Inhibiting TDO/TDO2 reduces neurodegeneration and improves motor performance in fly models of Huntington's, Alzheimer's, and Parkinson's disease (1). - TDO2 knockout in mice may decrease anxiety-like behaviors and affect locomotor activity, though effects in psychiatric disorders require further investigation (2). |
| What roles do amino acid metabolism and its dysregulation play in aging and neurodegeneration? | - Disrupted amino acid metabolism compensates for energy deficits in Alzheimer's disease but eventually leads to toxicities that accelerate neurodegeneration (9). - Elevated amino acid metabolites, such as homocysteine, promote protein aggregation and neuronal damage in aging brains (8). |
| What neuroprotection mechanisms exist in aging flies and mammals? | - Enhancing autophagy or glial clearance mechanisms in flies prolongs lifespan and mitigates neurodegeneration, while age-related declines in these processes increase vulnerability (10, 12, 14). - Modulating brain immune responses, such as NF-κB signaling, influences neurodegeneration rates and longevity in flies (11). |
| Are there potential risks or limitations of targeting tryptophan metabolism in neurodegenerative disease? | - While TDO inhibition shows therapeutic promise, some reviews caution that long-term effects are not fully understood and that off-target consequences may arise (3). - Ido2 deficiency in mice, another enzyme in the pathway, can worsen motor deficits and inflammation in demyelinating disease models, indicating complexity in targeting these pathways (4). |
How does TDO2 inhibition impact neurodegeneration and neuromotor decline?
Several studies demonstrate that TDO2 inhibition reduces neurodegeneration and improves neuromotor outcomes in both invertebrate and mammalian models, supporting the new study's findings on SIRT6 loss leading to TDO2-driven pathology. However, while TDO2 knockout often yields protective effects, the behavioral outcomes can vary with context and disease model.
- TDO/TDO2 inhibition in Drosophila models of various neurodegenerative diseases leads to improved motor function and extended lifespan (1).
- Increased kynurenic acid and decreased neurotoxic metabolites are implicated in the protective effects seen with TDO2 inhibition (1).
- In TDO2 knockout mice, some studies report reduced anxiety-like behavior and altered locomotion, though not all behavioral changes reach statistical significance (2).
- The new study's reversal of neuromotor decline via TDO2 inhibition in SIRT6-deficient flies aligns closely with these results (1, 2, 3).
What roles do amino acid metabolism and its dysregulation play in aging and neurodegeneration?
Research shows that amino acid metabolism shifts in aging and diseased brains, serving as a temporary compensatory mechanism before contributing to neurotoxicity and disease progression. The new study's focus on tryptophan metabolism is consistent with broader evidence linking amino acid dysregulation to neurodegeneration.
- In Alzheimer's disease, amino acid catabolism can initially compensate for decreased glucose metabolism but eventually leads to harmful metabolite accumulation (9).
- Elevated homocysteine, another amino acid metabolite, is associated with increased protein aggregation and neurodegeneration, an effect preventable by promoting autophagy (8).
- The toxic effects of altered amino acid metabolism, including tryptophan and its downstream products, are a common feature of neurodegenerative conditions (5, 9).
- The SIRT6-TDO2 axis described in the new study highlights a specific molecular mechanism within this broader context (9, 8).
What neuroprotection mechanisms exist in aging flies and mammals?
Multiple protective mechanisms have been identified in aging models, including enhanced autophagy, effective glial clearance of neuronal debris, and regulated immune responses. These mechanisms often decline with age, increasing susceptibility to neurodegeneration—a phenomenon addressed in the current study by reversing damage via TDO2 inhibition.
- Promotion of autophagy in the nervous system extends lifespan and reduces neurodegeneration in Drosophila (10).
- The glial engulfment receptor Draper in flies helps clear neurotoxic amyloid and protects against behavioral deficits in Alzheimer's models (12).
- Boosting PI3K/Draper activity in aged fly glia restores efficient clearance of degenerating axons, slowing neurodegeneration (14).
- Modulation of innate immunity, such as NF-κB signaling, significantly affects lifespan and neurodegeneration rates in flies (11).
Are there potential risks or limitations of targeting tryptophan metabolism in neurodegenerative disease?
While TDO2 inhibition appears beneficial in experimental models, some reviews and experimental studies caution that long-term inhibition or manipulation of tryptophan-catabolizing enzymes may have unintended effects, including immune dysregulation or exacerbation of other disease processes.
- TDO inhibition may alleviate both motor and non-motor symptoms in Parkinson's models, but concerns remain about chronic inhibition's safety and systemic effects (3).
- Ido2 deficiency (another tryptophan-catabolizing enzyme) can worsen motor impairment and inflammation in demyelinating disease models, suggesting enzyme targeting must be context-specific (4).
- The complexity of amino acid metabolism in the brain underscores the need for precise and selective therapeutic approaches (3, 4).
- The reversibility of SIRT6/TDO2-mediated damage, as shown in the new study, supports the feasibility of targeting this pathway, but careful evaluation of long-term outcomes is warranted (3).
Future Research Questions
Despite advances in understanding the SIRT6-TDO2-tryptophan axis in neurodegeneration, several important questions remain. Future research should address the durability and broader applicability of these findings, the safety of targeting tryptophan metabolism, and the mechanisms underlying observed effects in different disease contexts.
| Research Question | Relevance |
|---|---|
| What are the long-term effects of TDO2 inhibition on brain function and health? | Long-term safety and efficacy are not fully established, and some studies suggest possible adverse outcomes with chronic TDO2 inhibition (3). Understanding these effects is critical for therapeutic development. |
| Does SIRT6 regulation of tryptophan metabolism affect human neurodegenerative diseases? | Most data are from animal models; studies in human tissue or clinical populations are needed to determine translational relevance and potential for human therapies (1, 9). |
| Are there differential effects of modulating TDO2 and other tryptophan-catabolizing enzymes on distinct neurodegenerative conditions? | Related studies suggest context-dependent effects, with some enzymes worsening while others ameliorate disease symptoms in different models (1, 3, 4). Comparative studies are needed to clarify these relationships. |
| How does age-related decline in autophagy interact with tryptophan metabolism in the brain? | Autophagy and amino acid metabolism are both implicated in neurodegeneration, but their interactions are not fully understood (8, 10). This knowledge could inform combination therapeutic strategies. |
| What are the systemic effects of targeting the kynurenine pathway enzymes in the central nervous system? | Since these enzymes also function in peripheral tissues, systemic effects and potential immune or metabolic consequences must be evaluated (3, 4). |