SULTA4A1 modulates synaptic development and function by promoting the formation of PSD-95/NMDAR complex

Abstract

24Sulfotransferase 4A1 (SULT4A1) is a cytosolic sulfotransferase, that is highly conserved across 25 species and extensively expressed in the brain. However, the biological function of SULT4A1 is 26 unclear. SULT4A1 has been implicated in several neuropsychiatric disorders, such as McDermid Syndrome and schizophrenia. Here, we investigate the role of SULT4A1 within neuron 28 development and function. Our data demonstrate that SULT4A1 modulates neuronal branching 29 complexity and dendritic spines formation. Moreover, we show that SULT4A1, by negatively 30 regulating the catalytic activity of Pin1 towards PSD-95, facilitates NMDAR synaptic expression 31 and function. Finally, we demonstrate that the pharmacological inhibition of Pin1 reverses the 32 pathological phenotypes of SULT4A1 knockdown neurons by specifically restoring dendritic spine 33 density and rescuing NMDAR-mediated synaptic transmission. Together, these findings identify 34 SULT4A1 as a novel player in neuron development and function by modulating dendritic 35 morphology and synaptic activity. 36 37 2006). Consistent with this, SULT4A1 protein expression was found to increase during neuronal 58 differentiation (Idris et al., 2019). Notably, SULT4A1-KO mice display severe neurological defects 59 including tremor, rigidity and seizure and the survival of pups during postnatal development is 60 strongly affected by loss of SULT4A1 (Garcia et al., 2018). 61A growing body of evidence supports SULT4A1 as a key player in neuronal maturation, and that 62 loss of SULT4A1 function can contribute towards neurodevelopmental disorders. For instance, 63 SULT4A1 haploinsufficiency has been linked to neurological symptoms of patients with Phelan-64McDermid Syndrome (PMS) (Disciglio et al., 2014), with SULT4A1 deletion strongly correlated to 65 lower developmental quotient (Zwanenburg et al., 2016). In addition, single nucleotide 66 polymorphisms (SNP) in SULT4A1 gene have been extensively linked to schizophrenia 67 susceptibility as well as severity of both psychotic and intellectual impairment, and antipsychotic 68 treatment response (Brennan and Condra, 2005, Meltzer et al., 2008, Ramsey et al., 2011. 69Altogether, these findings suggest a role of SULT4A1 in neuronal development and function and 70 altered expression as a potential contributing factor in multiple neurodevelopmental disorders. 71Despite this body of supporting literature, the role of SULT4A1 within neuronal development and 72 function remains unassessed. Our results provide evidence that SULT4A1 has an important role in 73 the regulation of neuronal morphology and synaptic activity. Our data suggest that this effect is 74 achieved through regulation, by direct protein-protein interaction, of the peptidyl-prolyl cis-trans 75 isomerase Pin1 at a synaptic level. Pin1 is an enzyme that binds to phosphorylated serine/threonine-76 proline motifs and catalyzes cis-to-trans isomerization of prolines (Ranganathan et al., 1997, Shen et 77 al., 1998, notably acting to regulate synaptic strength through...