Structural and functional impairments of polysialic acid by a mutated polysialyltransferase found in schizophrenia

Polysialic acid (polySia), a unique acidic glycan modifying neural cell adhesion molecule (NCAM), is known to regulate embryonic neural development and adult brain functions. Polysialyltransferase STX is responsible for the synthesis of polySia, and two single nucleotide polymorphisms (SNPs) of the coding region of STX are reported from schizophrenic patients: SNP7 and SNP9, respectively, giving STX(G421A) with E141K and STX(C621G) with silent mutations. In this study, we focused on these mutations and a binding activity of polySia to neural materials, such as brain-derived neurotrophic factor (BDNF). Here we describe three new findings. First, STX(G421A) shows a dramatic decrease in polySia synthetic activity on NCAM, whereas STX(C621G) does not. The STX(G421A)-derived polySia-NCAM contains a lower amount of polySia with a shorter chain length. Second, polySia shows a dopamine (DA) binding activity, which is a new function of polySia as revealed by frontal affinity chromatography for measuring the polySia-neurotransmitter interactions. Interestingly, the STX(G421A)-derived polySia-NCAM completely loses the DA binding activity, whereas it greatly diminishes but does not lose the BDNF binding activity. Third, an impairment of the polySia structure with an endosialidase modulates the DA-mediated Akt signaling. Taken together, impairment of the amount and quality of polySia may be involved in psychiatric disorders through impaired binding to BDNF and DA, which are deeply involved in schizophrenia and other psychiatric disorders, such as depression and bipolar disorder.