Reduced Cystathionine γ-lyase Levels May Contribute Meaningfully to Age-Related Neurodegeneration
Cystathionine γ-lyase (CSE) levels are reduced with age, and researchers here show that removing CSE entirely in mice reproduces aspects of brain aging. That isn't enough to prove that the smaller reductions that take place with age do in fact make a meaningful contribution to neurodegeneration, but it is sufficient to justify greater attention and further research into to the mechanisms involved. The researchers chose to focus on CSE because it is involved in the production of hydrogen sulfide (H2S) in the brain. You may recall that the ability of increased H2S to be somewhat protective in the context of aging, such as via effects on inflammation and autophagy, has grown as a topic of interest in recent years. It is hard to effectively deliver H2S to the brain, however, as both normal and beneficial levels are very low; it is arguably better to try to adjust the operation of the biochemistry responsible for producing H2S instead.
Once considered to function predominantly in the peripheral systems, cystathionine γ-lyase (CSE) is emerging as a key player in neuroprotection. Prior studies had considered cystathionine β-synthase (CBS) to be the principal enzyme governing H2S signaling in the brain. In this study, through an integrated approach combining genetic, proteomic, biochemical, and behavioral studies, we demonstrate that CSE is crucial for maintaining brain homeostasis and that loss of CSE is sufficient to trigger cognitive deficits.
CSE, the enzyme responsible for neuronal cysteine and hydrogen sulfide production, is dysregulated in aging and neurodegenerative diseases including Alzheimer's disease and Huntington's disease, both marked by cognitive decline in addition to motor deficits. To determine whether CSE loss directly causes cognitive decline, we genetically ablated CSE in mice. This loss was sufficient to induce oxidative damage, compromise blood-brain barrier integrity, impair neurogenesis and neurotrophin signaling, and elicit cognitive deficits. Global proteomic analysis further revealed molecular alterations that contribute to impaired neurogenesis.
Our findings establish CSE as an essential guardian of homeostatic brain health and identify it as a potential therapeutic target for neurodegenerative disorders.