Lectin-Positive Spherical Deposits (SPD) Detected in the Molecular Layer of Hippocampal Dentate Gyrus of Dementia, Down’s Syndrome ,and Schizophrenia

Yates

Haroutunian

et al. 2017

Schizophrenia Research

Glycosylation is a post-translational modification that is an essential element in cell signaling and neurodevelopmental pathway regulation. Glycan attachment can influence the tertiary structure and molecular interactions of glycosylated substrates, adding an additional layer of regulatory complexity to functional mechanisms underlying central cell biological processes. One type of enzyme-mediated glycan attachment, fucosylation, can mediate glycoprotein and glycolipid cell surface expression, trafficking, secretion, and quality control to modulate a variety of inter- and intracellular signaling cascades. Building on prior reports of glycosylation abnormalities and evidence of dysregulated glycosylation enzyme expression in schizophrenia, we examined the protein expression of 5 key fucose-modifying enzymes: GDP-fucose:protein O-fucosyltransferase 1 (POFUT1), GDP-fucose:protein O-fucosyltransferase 2 (POFUT2), fucosyltransferase 8 (FUT8), fucosyltransferase 11 (FUT11), and plasma α-L-fucosidase (FUCA2) in postmortem superior temporal gyrus of schizophrenia (N = 16) and comparison (N = 14) subjects. We also used the fucose binding protein, Aleuria aurantia lectin (AAL), to assess α-1,6-fucosylated N-glycoprotein abundance in the same subjects. In schizophrenia we found increased expression of POFUT2, a fucosyltransferase uniquely responsible for O-fucosylation of thrombospondin-like repeat domains that is involved in a non-canonical endoplasmic reticulum quality control pathway. We also found decreased expression of FUT8 in schizophrenia. Given that FUT8 is the only α-1,6-fucosyltransferase expressed in mammals, the concurrent decrease in AAL binding in schizophrenia, particularly evident for N-glycoproteins in the ~52–58kDa and ~60–70kDa molecular mass ranges, likely reflects a consequence of abnormal FUT8 expression in the disorder. Dysregulated FUT8 and POFUT2 expression could potentially explain a variety of molecular abnormalities in schizophrenia.

Section: Discussionmentioning

confidence: 99%

Altered fucosyltransferase expression in the superior temporal gyrus of elderly patients with schizophrenia

Yates

Haroutunian

et al. 2017

Schizophrenia Research

“…Several neurotransmitter receptors, transporters, and associated molecules with atypical patterns of glycosylation have been identified in schizophrenia brain (Barbeau et al, 1995;Bauer et al, 2010;Gilabert-Juan et al, 2012;Mueller et al, 2014;Tucholski et al, 2013bTucholski et al, , 2013aVarea et al, 2012). Transcript-level studies have found mRNA levels of some glycosylation enzymes altered in this illness, and abnormal expression of specific glycan structures and monosaccharides in patient cerebrospinal fluid and blood serum have been reported (Ikemoto, 2014;Maguire et al, 1997;McAuley et al, 2012;Mueller et al, 2018;Narayan et al, 2009;Stanta et al, 2010). Previous glycobiology research in schizophrenia has focused on abnormal glycan expression and altered glycosylation of substrate proteins, while mechanisms which underlie glycosylation defects have not been as extensively explored.…”

mentioning

confidence: 99%

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

Mallepalli

Meador‐Woodruff

2019

Preprint

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.

“…Our lab has previously hypothesized that deficits of neurotransmission are not only due to abnormal expression of neurotransmitterassociated molecules, but may also result from abnormal receptor targeting and subcellular localization (Hammond et al, 2011;Mueller et al, 2015). Glycosylation is a PTM that plays a pivotal role in protein trafficking and subcellular targeting and has been shown in multiple studies to be abnormal in schizophrenia (Berretta, 2012;Ikemoto, 2014;Mueller et al, 2014;Narayan et al, 2009;Pantazopoulos et al, 2013;Sato and Kitajima, 2013;Stanta et al, 2010;Tucholski et al, 2013bTucholski et al, , 2013a.…”

mentioning

confidence: 99%

Glycosylation enzyme mRNA expression in dorsolateral prefrontal cortex of elderly patients with schizophrenia: Evidence for dysregulation of multiple glycosylation pathways

et al. 2018

Preprint

Altered protein post-translational modifications such as glycosylation have become a target of investigation in the pathophysiology of schizophrenia. Disrupted glycosylation associated processes including atypical sphingolipid metabolism, reduced polysialylation of cell adhesion molecules, abnormal proteoglycan expression, and irregular glycan synthesis and branching have also been reported in this disorder. These pathways are regulated by the expression of glycosidases and glycosyltransferases, classes of enzymes which comprise approximately 2% of the genome. Many glycosylation enzymes can participate in multiple glycosylation pathways and dysregulation of enzyme expression could represent a common mechanism leading to a variety of glycan processing deficits in schizophrenia. In matched pairs of elderly schizophrenia and comparison subject (N = 12 pairs) dorsolateral prefrontal cortex, we measured mRNA levels of 84 key glycosylation enzymes by qPCR array. We found dysregulated transcript expression of 36 glycosylation enzymes from 12 functional categories. All of the abnormally expressed enzymes demonstrated increased transcript expression in schizophrenia, and many altered enzymes are known to modify substrates that have been previously implicated in the pathophysiology this illness. These findings suggest that abnormal glycosylation enzyme expression in schizophrenia may contribute to dysregulation of multiple glycosylation pathways, and disruptions of these central cell signaling processes may underlie a variety of deficits in schizophrenia.