Altered protein expression of galactose and N-acetylgalactosamine transferases in schizophrenia superior temporal gyrus

Abstract

Abnormal glycosylation in schizophrenia brain has been previously implicated in disruptions to protein trafficking, localization, and function. Glycosylation is an enzyme-mediated posttranslational modification and, along with reports of altered glycan biosynthesis and abnormal glycan levels in peripheral fluids, growing evidence for altered glycosylation pathway activity in schizophrenia prompted investigation of specific enzymes which may be responsible for these abnormalities. Glycosylation is a highly variable yet tightly controlled cellular process and, depending on the molecule(s) affected, altered glycan modifications can influence the trajectory of many key functional pathways. In a preliminary gene array study, abnormal transcript expression of 36 glycosylation-associated enzymes was identified in schizophrenia brain. Subsequently, protein expression abnormalities of enzymes which act on glucose (UGGT2), mannose (EDEM2), fucose (FUT8, POFUT2), and N-acetylglucosamine (MGAT4A, B3GNT8) have been reported in this illness. The current study investigates protein expression levels by western blot analysis of the galactose and N-acetylgalactosamine (GalNAc) transferases B3GALTL1, B4GALT1, C1GALT1, GALNT2, GALNT7, GALNT16, and GALNTL5, as well as a related chaperone protein, COSMC, in superior temporal gyrus of age-and sex-matched pairs of schizophrenia and non-psychiatrically ill comparison subjects (N = 16 pairs). In schizophrenia, reduced β-1,4-galactosyltransferase 1 (B4GALT1) and polypeptide GalNAc-transferase 16 (GALNT16) were identified. These findings add support to the hypothesis that dysregulated glycosylation-associated enzyme expression contributes to altered protein glycosylation and downstream substrate-specific defects in schizophrenia.

Post-translational protein modifications in schizophrenia

“…83 A recent study in schizophrenia postmortem STG found B4GALT1 protein levels reduced, but the patients included in the study were elderly subjects who had primarily been treated with first generation antipsychotics. 72 Together, these reports suggest that both first and second generation antipsychotic medications alter glycosylation pathway activity but may do so via different mechanisms.…”

“…Glycosylation enzymes with reported gene and protein expression differences in schizophrenia brain are summarized from refs. [52][53][54][55]70,72 The direction of gene expression differences in schizophrenia for some enzymes were not specified and are indicated with an asterisk (*). Genes which do not demonstrate differential expression in schizophrenia are listed only if both gene and protein expression of the enzyme have been measured.…”

“…69,71 The enzyme GALNT16 is involved in the substratespecific synthesis of O-GalNAc glycans and protein expression of this enzyme has been found reduced in schizophrenia STG. 72 Some O-glycan subtypes precisely modify proteins containing specific structural elements, such as the cysteine knots in epidermal growth factor (EGF)-like or thrombospondin-like repeat (TSR) domains. O-fucosylation and/or O-glucosylation of EGF and EGF-like domain-containing proteins occurs in the ER, and stabilizes the amino acid chain to facilitate correct disulfide bond formation to produce the knot structure (Fig.…”