SULT4a1, a novel neuroprotective protein in stroke

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.

Grant Number: 5R01NS119479-05
NIH Institute/Center: NIH
Principal Investigator: Shaida Andrabi