Role of Protein Glycosylation in Schizophrenia: Mechanisms, Neurotransmitter Dysregulation and Therapeutic Implications

Abstract

Glycosylation involved in protein folding, endocytosis, molecular trafficking, receptor activation, cell adhesion, and signal transduction is a crucial post-translational change. Dysregulated glycosylation has been implicated in several neurological and psychiatric disorders including schizophrenia. Although its precise etiology remains unclear, prevailing hypothesis emphasize dysregulation of major neurotransmitter systems including dopamine, glutamate, and serotonin. Neuroanatomical alterations including grey matter reduction and decreased synaptic density have also been consistently reported. The review summarizes evidence that implicates several elements of glutamatergic neurotransmission abnormalities in N-linked glycosylation to disrupted glutamatergic neurotransmission in schizophrenia. Glycosylation patterns have also been found to be altered in the glutamate receptor subunits with the AMPA (GluR2, GluR4), NMDA, and kainate (GluR6) receptors being reported to be impaired in glycan maturation and receptor transport. The observed high sensitivity of Endoglycosidase H in some of the subunits reflects the retention of immature high-mannose glycans, which result in the failure of glycogen to process through the endoplasmic reticulum- Golgi pathway. Moreover, down-regulation of glycosyltransferases such as MGAT4A and B3GNT8 in the dorsolateral prefrontal cortex might interfere with N-glycan branching and complex glycan production which is a possible upstream enzymatic defect. Furthermore, glutamate reuptake may be hampered by a decrease in the glycosylation of excitatory amino acid transporters (EAAT1 and EAAT2), which is a contributor to an imbalance in the synapses and excitotoxic susceptibility. Taken together, these results are in favor of a mechanistic theory, with modified glycosylation being the source of impaired receptor maturation, localization, and transporter stability, and, eventually, glutamatergic dysregulation. Glycosylation-dependent molecular pathways provide fresh insights into the creation of biomarkers and treatment targets for schizophrenia.