Scientists have identified a crucial brain enzyme that may be a primary contributor to early cognitive decline and neurodegeneration. Cystathionine γ-lyase (CSE) is an enzyme involved in the synthesis of hydrogen sulfide (H2S), a gaseous signaling molecule important for brain function. Along with two other enzymes, cystathionine β-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (3-MST), CSE plays a role in regulating stress responses, energy metabolism, and neuron-to-neuron communication, thereby supporting overall brain health.
CSE is of particular importance, as it can regulate a chemical reaction, S-sulfhydration, which modifies proteins and protects them against oxidative stress-induced damage. It is essential for normal cell function and helps protect sensitive brain proteins from irreversible damage. Such a reduction in CSE activity has previously been reported in the case of Alzheimer’s disease, but its role in cognition was not evident. This was investigated by studying mice genetically engineered to be CSE-deficient.
These mice also showed specific learning and memory impairment at 6 months of age, as assessed using the Barnes maze, a spatial memory test. Interestingly, the deficits were not caused by movement challenges, sensory impairment, or low body weight. Mice that had CSE at a younger age performed well, indicating that cognitive deterioration did not occur rapidly.
The subsequent analysis revealed that the CSE loss resulted in ubiquitous molecular alterations in the hippocampus, an area of the brain indispensable to memory. Proteomic profiling identified hundreds of altered proteins, with particular attention to those involved in synaptic function, transport, and oxidative stress adaptation. Some of these developments were very similar to those found in human brains with Alzheimer’s disease and Parkinson’s disease.
In mice with CSE deficiency, oxidative stress measures were elevated with a high degree of significance. There was lipid peroxidation, evidence of protein oxidation, and DNA damage in the brain, indicative of heightened cellular stress. The antioxidant enzymes were also elevated, indicating a failed attempt by the brain to fight this destruction. Moreover, there existed excess and abnormal concentrations of iron, which are among the established causes of neuronal toxicity and cell death in neurodegenerative diseases.
This was among the most vivid findings: the blood-brain barrier, which is the protective lining of the blood against its penetration into the brain, was damaged. Under the microscope, the brain capillaries were observed to be torn, and the cells that supported them were damaged. These structural changes allowed the immune proteins to leak into the brain tissue, which is an indication of a weak barrier. Since blood–brain barrier breakdown is one of the earliest events in cognitive decline, this finding strongly highlights the protective role of CSE. The brain was also incapable of producing new neurons due to CSE loss. The number of neural stem cells in the hippocampus of the affected mice was low, the number of newly formed neurons was also low, and the expression of genes that help in brain plasticity was also low.
Significant pathways of signaling that involve CREB and BDNF, which are critical in learning and memory, were also compromised. Overall, these findings show that CSE is a major trigger of brain well-being. Its insufficiency causes a cascade of oxidative stress, DNA and iron damage, breakdown of the blood-brain barrier, impaired neurogenesis, and memory loss.
The researchers show that the CSE functional recovery or related low-level H2S signals may be an effective way to delay cognitive aging and avoid neurodegenerative diseases. Despite the fact that the concentration of the hydrogen sulfide was not directly measured, researchers found that the earlier study proves that the augmentation of this pathway is adequate to mend the protective proteins modifications and reduce neurodegeneration. The future directions will be searching into the treatment modes that can increase the activity of CSE or downstream signaling, which can help the brain to stand firm, support memory, and delay the emergence of age-related cognitive disorders in human beings around the world today.
References: Chakraborty S, Tripathi SJ, Vázquez-Rosa E, et al. Cystathionine γ-lyase is a major regulator of cognitive function through neurotrophin signaling and neurogenesis. Proc Natl Acad Sci U S A. 2025;122(52):e2528478122. doi:10.1073/pnas.2528478122
