Israeli and European scientists recently uncovered a new molecular mechanism that could explain why aging and neurological diseases often cause sleep problems, mood changes, and memory loss. This discovery centers on an enzyme called sirtuin 6, or SIRT6. Researchers say targeting SIRT6 could open new ways to treat neurodegenerative conditions.^[1] ### Unlocking the Role of SIRT6 in Brain Health The research team, led by Professor Haim Toiber, identified SIRT6 as a key regulator in how the brain processes tryptophan. Tryptophan is an important amino acid known for its role in producing serotonin and melatonin, which affect sleep and mood. However, the scientists found tryptophan also fuels a separate pathway that creates cellular energy. A healthy balance between these two pathways is vital for brain function.^[1] SIRT6 acts as a gatekeeper for this tryptophan metabolism. When SIRT6 is not working correctly, it disrupts this balance. This malfunction leads to the brain changes seen in aging and neurodegenerative diseases. The study, published in the journal *Nature Communications*, showed SIRT6 is an active metabolic switch in the brain, not just a passive marker of aging.^[1] The scientists used human cell lines, mice, and fruit fly models in their study. They found that in fruit flies lacking SIRT6, brain damage occurred. Crucially, they also showed this damage is not unavoidable. By blocking a second enzyme, TDO2, in these fruit flies, they significantly prevented motor skill decline and reduced harmful changes in brain tissue. TDO2 is an enzyme that pushes tryptophan into the problematic kynurenine pathway.^[1] Professor Toiber emphasized the importance of these findings. "Our research positions the enzyme SIRT6 as a critical and primary drug target to combat degenerative brain pathology," Toiber said.^[1] "These findings change the way we understand the relationship between aging and brain function. It is not simply wear and tear, but a specific metabolic malfunction that can be corrected."^[1] This suggests that therapies focusing on SIRT6 could address the root causes of brain decline. ### A New Approach for Parkinson's Disease In a separate but equally important development, Gain Therapeutics announced positive results from a Phase 1b clinical trial for a new Parkinson's disease treatment. The drug, called GT-02287, is an orally taken small molecule that can reach the brain. It works by restoring the function of the lysosomal enzyme glucocerebrosidase, or GCase.^[2] GCase activity is often impaired in Parkinson's patients, especially those with GBA1 gene mutations. Researchers believe GT-02287 helps correct enzyme misfolding. This action improves the health of lysosomes and mitochondria, which are crucial cell components. By doing so, the drug aims to reduce the build-up of alpha-synuclein, a protein linked to Parkinson's, and decrease brain inflammation.^[2] The trial results showed that GT-02287 lowered levels of glucosylsphingosine (GluSph) in the cerebrospinal fluid of Parkinson's patients. Elevated GluSph is a marker linked to GCase dysfunction and alpha-synuclein aggregation. This reduction suggests that GT-02287 successfully increased GCase activity in the brain.^[2] Gene Mack, president and CEO of Gain Therapeutics, highlighted the significance of these findings. "To our knowledge, GT-02287 is the first GCase modulator to demonstrate a reduction of GluSph in CSF in people with PD, providing downstream evidence of GCase enhancement in the brain," Mack said.^[2] "Further, we believe that reduction in brain GluSph levels will have a direct impact on neuronal health and translate to clinically observable improvements."^[2] The Phase 1b trial included 21 patients, with 15 continuing into a nine-month extension study expected to finish in September 2026.^[2] ### Broader Impact on Neurodegenerative Conditions Neurodegenerative diseases, like Alzheimer's and Parkinson's, are major health challenges for the aging global population. These conditions involve the progressive loss of brain cells, leading to severe memory loss, cognitive decline, and movement problems. Current treatments often only manage symptoms and do not stop the underlying disease progression.^[3] These new enzyme discoveries offer hope for more effective treatments. Understanding how enzymes like SIRT6 and GCase influence brain metabolism and protein function provides scientists with specific targets for drug development. Instead of broadly addressing symptoms, these new approaches aim to correct fundamental cellular malfunctions that drive neurodegeneration. Beyond the SIRT6 and GCase findings, other recent enzyme discoveries also point to new therapeutic avenues. Scientists at St Vincent's Institute of Medical Research in Melbourne, Australia, for instance, mapped the 3D structure of the PLD3 enzyme, which is linked to the amyloid beta plaques seen in Alzheimer's. This breakthrough allows for more precise drug design. Professor Michael Parker, who led the study, said, "This structure is highly significant as it gives us an edge in discovering molecules that will modulate the activity of the enzyme that might be developed into drugs."^[4] In the UK, researchers at the University of Leeds and Lancaster University found that reducing the activity of the PDE4B enzyme improved memory and brain glucose metabolism in Alzheimer's mouse models. Dr. Steven Clapcote, lead researcher, noted, "This raises the prospect that reducing PDE4B activity may protect against cognitive impairment not only in Alzheimer's disease but also in other forms of dementia, such as Huntington's disease."^[5] Even protein clumps, long thought to be inert waste in diseases like Parkinson's and Alzheimer's, were found by Rice University researchers to act like enzymes themselves, actively draining energy from brain cells.^[6] ### Future Outlook for Brain Health These breakthroughs highlight a growing understanding that neurodegenerative diseases are not simply due to "wear and tear." Instead, they involve specific metabolic and enzymatic malfunctions that can potentially be corrected. The focus on enzymes that control critical cellular processes, like metabolism, waste removal, and energy production, represents a significant shift in research.^[1][6][7] The next steps for these discoveries include further preclinical testing and advancing promising compounds into more human clinical trials. Researchers hope that by targeting these specific enzymes, they can develop drugs that not only alleviate symptoms but also slow, halt, or even reverse the progression of devastating brain diseases. This could lead to a future where neurodegenerative conditions are managed more effectively, improving the quality of life for millions worldwide. New enzyme discoveries are paving the way for targeted therapies that could fundamentally change how doctors treat aging-related brain disorders.

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