Stroke remains a leading cause of death and morbidity in the USA and lacks effective therapeutic interventions. Redox imbalance and mitochondrial dysfunction are considered as leading causes of cell death in stroke. Identification of novel therapeutic targets that restore redox homeostasis, mitochondrial function, and cell survival is a critical need. Deregulation in peroxiredoxins (PRDXs) is one of the mechanisms leading to redox imbalance and mitochondrial dysfunction. PRDXs act as double-edged swards that the highly neuroprotective when inside the cells in reduced forms. However, when oxidized and released from damaged/dead cells, PRDXs can lead to secondary cell death signaling via inflammatory responses. Therefore, the regulation of PRDXs in stroke is a vital neuroprotective strategy. We identified that regulation of PRDXs by SULT4a1 (relatively less studies neuronal protein) is a critical neuroprotective function of SULT4a1 and may have a vital neuroprotective role in stroke. Loss of SULT4a1 in mouse neurons leads to the accumulation of oxidized PRDXs with subsequent redox imbalance, mitochondrial dysfunction, and cell death. SULT4a1 can interact with PRDX1, PRDX2, PRDX3, and PRDX5. These PRDXS (cytosolic-PRDX1 and PRDX2, and mitochondrial-PRDX3 and PRDX5) are crucial for cytosolic and mitochondrial redox homeostasis via detoxification of peroxides. During this process, PRDXs are oxidized and must be recycled back to reduced forms. Expression of SULT4a1 increases the levels of reduced PRDXs in peroxide-treated cells. SULT4a1 protein levels decrease in stroke via the ubiquitin proteasomal system. However, the role of SULT4a1 in stroke or the mediators that lead to loss of SULT4a1 in stroke are not known. We will use oxygen- glucose deprivation in mouse cortical neurons and a middle cerebral artery occlusion (MCAO) model of stroke in mice to identify the neuroprotective roles of SULT4a1 in stroke. We propose the following four aims to study the role of SULT4a1 in stroke:
Specific Aim #1 : Can SULT4a1 maintain redox homeostasis via PRDXs in stroke? Specific Aim #2: Can SULT4a1 rescue mitochondrial function in stroke? Specific Aim #3: Is SULT4a1 neuroprotective in stroke? Specific Aim #4: Identify the mechanisms leading to loss of SULT4a1 in stroke Our supporting data strongly favor our hypothesis and the proposed aims. Combining viral-mediated expression of SULT4a1 with Seahorse Flux analysis, electron microscope imaging, proximity ligation assays, proximity-dependent biotin identification, live-cell imaging, and MRI imaging in experimental models of stroke represents a novel approaches to identify the neuroprotection by SULT4a1 in stroke. These studies will reveal essential knowledge about the role of the novel SULT4a1-dependent pathways in stroke, and determine whether SULT4a1 can represent a credible target for therapeutic intervention in stroke.

Public Health Relevance

SULT4a1 protein levels significantly decrease in stroke and potentially lead to mitochondrial dysfunction via alteration in peroxiredoxin-dependent redox homeostasis. SULT4a1 is essentially required for neural survival. SULT4a1 protects against peroxide-induced cell injury and oxygen glucose deprivation-mediated cell death in neurons, making SULT4a1 a strong candidate for evaluation of neuroprotection in stroke.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Neural Oxidative Metabolism and Death Study Section (NOMD)
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Bosetti, Francesca
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University of Alabama Birmingham
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United States
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