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 neuron development and function. Our data demonstrate that SULT4A1 modulates neuronal branching complexity and dendritic spines formation. Moreover, we show that SULT4A1, by negatively regulating the catalytic activity of Pin1 toward PSD-95, facilitates NMDAR synaptic expression and function. Finally, we demonstrate that the pharmacological inhibition of Pin1 reverses the pathologic phenotypes of neurons knocked down by SULT4A1 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 evidence has 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.

磺基转移酶4A1（SULT4A1）是一种胞质磺基转移酶，在整个物种中高度保守，并在大脑中广泛表达。但是，SULT4A1的生物学功能尚不清楚。SULT4A1与多种神经精神疾病有关，例如Phelan–McDermid综合征和精神分裂症。在这里，我们调查神经细胞发育和功能中SULT4A1的作用。我们的数据表明，SULT4A1调节神经元分支的复杂性和树突棘的形成。此外，我们表明，SULT4A1通过负调节Pin1对PSD-95的催化活性，促进NMDAR突触的表达和功能。最后，我们证明，Pin1的药理学抑制作用可通过特异性地恢复树突棘密度并拯救NMDAR介导的突触传递来逆转被SULT4A1击倒的神经元的病理表型。总之，这些发现通过调节树突形态和突触活性将SULT4A1鉴定为神经元发育和功能的新型参与者。

重要声明磺基转移酶4A1（SULT4A1）是在神经元中高度表达的大脑特异性磺基转移酶。不同的证据表明，SULT4A1在神经元功能中具有重要作用，而SULT4A1改变的表达可能是多种神经发育障碍的一个促成因素。但是，SULT4A1在哺乳动物脑中的功能仍不清楚。在这里，我们证明SULT4A1在隔离Sin1的突触后位点高表达，从而防止了它对突触传递的负面作用。这项研究揭示了SULT4A1在NMDA受体活性的调节中的新作用，并强烈有助于解释在携带SULTA41基因缺失的患者中观察到的神经元功能障碍。