A role for the cystathionine-β-synthase /H2S axis in astrocyte dysfunction in the aging brain
Anindya Dey,
Pijush Kanti Pramanik,
Shailendra Kumar Dhar Dwivedi,
Fiifi Neizer-Ashun,
Tamas Kiss,
Abhrajit Ganguly,
Heather Rice,
Priyabrata Mukherjee,
Chao Xu,
Mohiuddin Ahmad,
Anna Csiszar,
Resham Bhattacharya
Affiliations
Anindya Dey
Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
Pijush Kanti Pramanik
Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
Shailendra Kumar Dhar Dwivedi
Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA; Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
Fiifi Neizer-Ashun
Department of Cell Biology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
Tamas Kiss
Vascular Cognitive Impairment and Neurodegeneration Program, Oklahoma Center for Geroscience and Healthy Brain Aging, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Pediatric Center, Semmelweis University, Budapest, Hungary
Abhrajit Ganguly
Section of Neonatal-Perinatal Medicine, Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
Heather Rice
Department of Biochemistry & Molecular Biology, Oklahoma Center for Geroscience & Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
Priyabrata Mukherjee
Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA; Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
Chao Xu
Department of Biostatistics and Epidemiology, Hudson College of Public Health, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
Mohiuddin Ahmad
Department of Cell Biology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
Anna Csiszar
Vascular Cognitive Impairment and Neurodegeneration Program, Oklahoma Center for Geroscience and Healthy Brain Aging, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
Resham Bhattacharya
Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA; Department of Cell Biology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA; Corresponding author. Department of Obstetrics and Gynecology Peggy and Charles Stephenson Cancer Center, OUHSC, 975 NE 10th Street, BRC-1409B, Oklahoma City, OK, 73104, USA.
Astrocytic dysfunction is central to age-related neurodegenerative diseases. However, the mechanisms leading to astrocytic dysfunction are not well understood. We identify that among the diverse cellular constituents of the brain, murine and human astrocytes are enriched in the expression of CBS. Depleting CBS in astrocytes causes mitochondrial dysfunction, increases the production of reactive oxygen species (ROS) and decreases cellular bioenergetics that can be partially rescued by exogenous H2S supplementation or by re-expressing CBS. Conversely, the CBS/H2S axis, associated protein persulfidation and proliferation are decreased in astrocytes upon oxidative stress which can be rescued by exogenous H2S supplementation. Here we reveal that in the aging brain, the CBS/H2S axis is downregulated leading to decreased protein persulfidation, together augmenting oxidative stress. Our findings uncover an important protective role of the CBS/H2S axis in astrocytes that may be disrupted in the aged brain.
