Cystathionine γ-lyase is a major regulator of cognitive function through neurotrophin signaling and neurogenesis
Cystathionine 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.
Authors
- Bindu D. Paul (ORCID: https://orcid.org/0000-0002-1862-6103)
- Bobby Thomas (ORCID: https://orcid.org/0000-0001-9244-9726)
- Kalyani Chaubey (ORCID: https://orcid.org/0000-0002-6378-6739)
- Sunil Jamuna Tripathi (ORCID: https://orcid.org/0000-0001-9107-2437)
- Benjamin C. Orsburn (ORCID: https://orcid.org/0000-0002-0774-3750)
- Hisashi Fujioka (ORCID: https://orcid.org/0000-0001-8511-7141)
- Thibaut Vignane (ORCID: https://orcid.org/0000-0002-3377-3187)
- Andrew A. Pieper (ORCID: https://orcid.org/0000-0001-6299-6577)
- Suwarna Chakraborty (ORCID: https://orcid.org/0000-0001-9456-4322)
- Randy J Nelson
- SH Snyder
- Andrew A. Pieper
- Emiko Miller
- Edwin Vázquez-Rosa
- Richa Tyagi
- Zachary M. Weil
Institutions
- West Virginia University (US)
- Johns Hopkins University (US)
- Medical University of South Carolina (US)
- Discovery Institute (US)
- Johns Hopkins Medicine (US)
- Discovery Centre (CA)
- Blanchette Rockefeller Neurosciences Institute (US)
- MUSC Hollings Cancer Center (US)
- University Hospitals Cleveland Medical Center (US)
- Geriatric Research Education and Clinical Center (US)
- Drug Discovery Laboratory (Norway) (NO)
- Lieber Institute for Brain Development (US)
- Case Western Reserve University (US)
- University of Glasgow (GB)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2025-12-26
- DOI
- https://doi.org/10.1073/pnas.2528478122
- Primary Topic
- Sulfur Compounds in Biology
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- U.S. Department of Defense
- U.S. Department of Veterans Affairs
- American Heart Association
- Johns Hopkins University
- Case Western Reserve University
- National Institutes of Health
- National Institute on Aging