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Global proteomic profiling identifies molecular alterations underlying impaired neurogenesis, positioning CSE as a guardian of brain homeostasis and a potential therapeutic target.",{"@graph":14,"@context":72},[15,34,55],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/research-report/","Research & 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happens when CSE is genetically depleted in mice?","Question",{"text":62,"@type":63},"Loss of CSE is sufficient to induce oxidative damage, compromise blood–brain barrier integrity, impair neurogenesis and neurotrophin signaling, and elicit cognitive deficits.","Answer",{"name":65,"@type":60,"acceptedAnswer":66},"Which mechanisms connect CSE loss to cognitive impairment?",{"text":67,"@type":63},"CSE depletion triggers oxidative damage and disrupts neurotrophin signaling and neurogenesis, with proteomic changes that contribute to reduced neurogenic capacity.",{"name":69,"@type":60,"acceptedAnswer":70},"How does the study redefine CSE’s role in the brain?",{"text":71,"@type":63},"CSE is shown to be crucial for brain homeostasis, elevating it from a predominantly peripheral enzyme to an essential contributor to brain health and a potential therapeutic 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through neurotrophin signaling and neurogenesis  \nSuwarna Chakrabortya,1, Sunil Jamuna Tripathia,1, Edwin Vázquez-Rosab,c,d,e , Kalyani Chaubeyb,c,d,e , Hisashi Fujiokaf, Emiko Millerb,c,d,e,g, Richa Tyagih, Thibaut Vignanei, Sudarshana M. Sharmaj, Bobby Thomask, l, m, n, Zachary M. Weilo , Randy J. Nelsono , Milos R. Filipovici, p, Benjamin C. Orsburna,2,  \nSolomon H. Snydera, h,q,3, Andrew A. Pieperb,c,d,e, r,s, and Bindu D. Paula, h,q,t,3 Affiliations are included on p. 11.  \nContributed by Solomon H. Snyder; received October 8, 2025; accepted November 21, 2025; reviewed by Péter Nagy and Csaba Szabo  \nCystathionine γ-lyase (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.  \ncystathionine gamma lyase | neurogenesis | cognition | neurotrophin | blood–brain barrier  \nCystathionine γ-lyase (CSE) is a key enzyme in the reverse transsulfuration pathway (Fig. 1A), the sole mammalian biosynthetic enzyme for the semiessential amino acid cysteine and oneof three enzymes that produces the gasotransmitter hydrogen sulfide (H2S) in the brain (1) . Two other enzymes, cystathionine β-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (3-MST), also generate H2S in the brain, with CSE predominantly neuronal, 3-MST present in both neurons and astrocytes, and CBS localized to glial cells (2, 3) . CSE utilizes either cysteine or homocysteine as a substrate to generate the gasotransmitter, which signals via the posttranslational modification termed S-sulfhydration/persulfidation (4–7) . S-sulfhydration is widespread throughout the body and regulates diverse physiological processes, including responses to stress stimuli, mitochondrial function, and neuronal signaling (4). At the molecular level, S-sulfhydration modulates the activity of numerous proteins, including key metabolic proteins and neuroprotective enzymes such as glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and the E3-ubiquitin ligase parkin (8–10) . It influences organellar stress responses and cellular signaling (11–16), and also protects cysteine residues from irreversible oxidation (17–19) .  \nAcross species, aging is associated with decreased S-sulfhydration, increased cysteine oxidation, and reduced CSE levels (17). Elevated CSE expression and H2S signaling have also been linked to longevity strategies, including dietary restriction and mTOR inhibition (20–22), and CSE has been identified as a prolongevity gene in several screens (23, 24). We and others have previously shown that H2S donors are neuroprotective in preclinical models of Alzheimer’s disease (AD) driven by human genetic mutations known to cause heritable disease and also that brain CSE and S-sulfhydration decline in preclinical models of aging and AD (10, 17, 25, 26). Dysregulation of the transsulfuration pathway and CSE was also observed in several other neurodegenerative states including Huntington’s disease (HD), Parkinson’s disease (PD), and ataxia (9, 27, 28). While insufficient H2S production can impair neural function, excessive H2S levels are equally harmful, as demonstrated in Down syndrome (29, 30).  \nHistorically, CBS and 3-MST have been consi","cbCaijA8H25Hzc9C","https://ap.wps.com/l/cbCaijA8H25Hzc9C","pdf",7186878,12,"English","# Results\n## CSE Depletion Causes Premature Cognitive Impairment\n# Significance","[{\"question\":\"What happens when CSE is genetically depleted in mice?\",\"answer\":\"Loss of CSE is sufficient to induce oxidative damage, compromise blood–brain barrier integrity, impair neurogenesis and neurotrophin signaling, and elicit cognitive deficits.\"},{\"question\":\"Which mechanisms connect CSE loss to cognitive impairment?\",\"answer\":\"CSE depletion triggers oxidative damage and disrupts neurotrophin signaling and neurogenesis, with proteomic changes that contribute to reduced neurogenic capacity.\"},{\"question\":\"How does the study redefine CSE’s role in the brain?\",\"answer\":\"CSE is shown to be crucial for brain homeostasis, elevating it from a predominantly peripheral enzyme to an essential contributor to brain health and a potential therapeutic target.\"}]","Cystathionine γ-lyase is a major regulator of cognitive function through neurotrophin signaling and neurogenesis | PDF",1790701451]