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bioRxiv · 10.1101/2025.04.07.647574

Sulfotransferase 4A1 (SULT4a1): A Novel Neuroprotective Protein in Stroke

Hossain, M. I.·Khan, J.·Lee, J. H.·Falany, C. N.·King, P. H.·Bolding, M.·Andrabi, S. A.
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Abstract

SULT4a1, a member of the cytosolic sulfotransferase family, is predominantly expressed in neurons and plays potentially vital roles in regulating neural survival and function. SULT4a1 protects against mitochondrial dysfunction and oxidative stress. SULT4a1 levels decrease in experimental stroke models and may play a critical neuroprotective role in mitigating neuronal injury caused by oxygen-glucose deprivation (OGD) and ischemic stroke, as shown in a transient middle cerebral artery occlusion (tMCAO) mouse model. In this study, we investigated the neuroprotective role of SULT4a1 in OGD and tMCAO and highlighted its expression pattern and involvement in maintaining mitochondrial function and reducing oxidative stress, two early pathophysiological features in stroke and related neuronal injury. Our data show that decreased SULT4a1 expression in OGD conditions and in the tMCAO mouse brain leads to enhanced neuronal damage, emphasizing the importance of SULT4a1 in preserving neuronal integrity. Loss of SULT4a1 alone was sufficient to decrease mitochondrial function in mouse cortical neurons. Notably, overexpression of SULT4a1 preserved mitochondrial function, reduced the loss of mitochondrial membrane potential, and diminished oxidative stress, as evidenced by lower reactive oxygen species (ROS) production and reduced protein carbonylation. These results indicate that modulating SULT4a1 expression in stroke could offer a promising strategy for preventing neuronal damage. Indeed, overexpression of SULT4a1 via stereotaxic injection of AAV9 into the mouse brain mitigated tMCAO-related brain injury and functional deficits over time. The findings of this study indicate that SULT4a1 may protect neurons in stroke and related brain injury, possibly by maintaining mitochondrial function and redox homeostasis through mechanisms that are still unknown. It is likely that SULT4a1 regulates neuroprotective processes in both the mitochondria and the cytosol. However, further research is needed to clarify the specific molecular pathways involved in its neuroprotective function.

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Hossain, M. I., Khan, J., Lee, J. H., Falany, C. N., King, P. H., Bolding, M., Andrabi, S. A.. 2025-04-07. Sulfotransferase 4A1 (SULT4a1): A Novel Neuroprotective Protein in Stroke. https://doi.org/10.1101/2025.04.07.647574

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