SULT4A1 Modulates Synaptic Development and Function by Promoting the Formation of PSD-95/NMDAR Complex

Abstract

Sulfotransferase 4A1 (SULT4A1) is a cytosolic sulfotransferase, that is highly conserved across species and extensively expressed in the brain. However, the biological function of SULT4A1 is unclear. SULT4A1 has been implicated in several neuropsychiatric disorders, such as Phelan-McDermid Syndrome and schizophrenia. Here, we investigate the role of SULT4A1 within neurons development and function. Our data demonstrates that SULT4A1 modulates neuronal branching complexity and dendritic spines formation. Moreover, we show that SULT4A1, by negatively regulating the catalytic activity of Pin1 towards PSD-95, facilitates NMDAR synaptic expression and function. Finally, we demonstrate that the pharmacological inhibition of Pin1 reverses the pathological phenotypes of SULT4A1-knocked down neurons by specifically restoring dendritic spine density and rescuing NMDAR-mediated synaptic transmission. Together, these findings identify SULT4A1 as a novel player in neuron development and function by modulating dendritic morphology and synaptic activity. SIGNIFICANCE STATEMENT Sulfotransferase 4A1 (SULT4A1) is a brain-specific sulfotransferase highly expressed in neurons. Different evidences suggested that SULT4A1 has an important role in neuronal function and that SULT4A1 altered expression might represent a contributing factor in multiple neurodevelopmental disorders. However, the function of SULT4A1 in the mammalian brain is still unclear. Here, we demonstrate that SULT4A1 is highly expressed at postsynaptic sites where it sequesters Pin1, preventing its negative action on synaptic transmission. This study reveals a novel role of SULT4A1 in the modulation of NMDA receptor activity and strongly contributes to explaining the neuronal dysfunction observed in patients carrying deletions of SULTA41 gene.

Sulfotransferase 4A1 activity facilitates sulfate-dependent cellular protection to oxidative stress

“…In addition, SULT4A1 expression stimulates yeast colony formation and growth in liquid media under fermentative (mitochondrial independent generation of ATP) and respiratory (mitochondria dependent generation of ATP) growth conditions. This SULT4A1 stimulated growth advantage in yeast could be related to similar events recently report by Culotta et al 34 . These authors reported that SULT4A1 is involved in regulating neuronal branching and dendritic spine formation, which was significantly reduced in cells that were SULT4A1 deprived 34 .…”

Integrated analysis of multi‐omics data on epigenetic changes caused by combined exposure to environmental hazards

“…22 Arborization has been reported to cause abnormal morphology and reduction in the number of dendrites. 23 Hypermethylation of the 5 0 untranslated region of FMR1 causes fragile X syndrome (FXS) 39 and FMR1 was found to be downregulated because of hypermethylation in the two combined exposure groups in our study. Thus, exposure to VOCs has a negative effect on the overall nervous system, and the effect is more pronounced in combination exposure.…”

“…Two genes (PML and ANKRD11) in the T group, two genes (FMR1 and NOTCH1) in the TX group, and eight genes (CNTNAP3, SULT4A1, CLIP2, CACNG8, WNT7B, GLS2, TP73, and FMR1) in the TEX group were confirmed to be downregulated, resulting in a decrease in the number and length of dendrites and axons 22 . Arborization has been reported to cause abnormal morphology and reduction in the number of dendrites 23 . Hypermethylation of the 5′ untranslated region of FMR1 causes fragile X syndrome (FXS) 39 and FMR1 was found to be downregulated because of hypermethylation in the two combined exposure groups in our study.…”

High performance single-cell gene regulatory network inference at scale: The Inferelator 3.0

“…The stress response TF Atf4 [51] is known to regulate neuronal GABA B receptor trafficking [52], and we identify it as a regulator of Rnf166, a RING-finger protein that promotes apoptotic cell death in neurons [53]. We also determine that Atf4 regulates the highly conserved cytosolic sulfotransferase Sult4a1, which modulates neuronal branching complexity and dendritic spine formation, and has been linked to neurodevelopmental disorders [54]. As the GRNs that have been learned for each cell type are sparse and consist of the highest-confidence regulatory edges, they are very amenable to exploration and experimental validation.…”