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Abstract

Background: Abnormalities in post-translational modifications (PTMs), such as glycosylation, ubiquitination, palmitoylation, and phosphorylation, have been implicated in the neuropathophysiology of schizophrenia (SCZ). A common PTM that plays a role in many different cellular events, such as cell recognition and interaction, intracellular signal transduction, cell surface enzymatic reactions, and bacterial or viral infections, is the addition of a glycosylphosphatidylinositol (GPI). GPIs are a class of complex glycolipids that anchor surface proteins and glycoproteins to the cell membrane. The GPI complex is synthesized in the endoplasmic reticulum (ER) and attached to proteins by the GPI transamidase complex. After attachment, the GPI anchor goes through several modification steps, including inositol deacylation by PGAP1, which is required for efficient export of GPI-anchored proteins (GPI-APs) from the ER and is used as a molecular mechanism for quality control of GPI-APs. Following these modification steps, the p24 family of proteins bind to GPI-APs, recognize their folding state, and facilitate GPI-AP export from the ER. Together, these steps facilitate protein folding, trafficking, and quality control of GPI-APs in the ER. Neuroligin 1 (NGLN1), a protein previously implicated in SCZ, is a GPI-AP and the following study examines its’ localization and the GPI-AP elements that may be contributing to an abnormality in NLGN1 trafficking.

Methods: In homogenate derived from the dorsolateral prefrontal cortex (DLPFC) of 15 pair-matched SCZ and comparison subjects, we measured expression of proteins involved in attachment (GPAA1), modification (PGAP1), and transport (p24) of GPI-APs. Additionally, we measured NLGN1 expression in subcellular fractions, specifically in fractions enriched for ER and synaptic membranes. To control for effects of chronic antipsychotic treatment, we repeated these findings in rats chronically treated with haloperidol.

Results: p24 protein expression was significantly decreased in the DLPFC of subjects with SCZ. While total expression of NLGN1 was not changed in subjects with SCZ, we observed an increase in NLGN1 expression in the ER-enriched fraction and a decrease in NLGN1 expression in the synapse-enriched fraction. These differences were not found in Haloperidol treated rats, suggesting that they are not an effect of antipsychotic treatment.

Conclusion: Decreased expression of p24 has been shown to inhibit ER export of GPI-APs. p24-induced reduction in ER export of GPI-APs could have major functional consequences on processes requiring GPI-APs. Supporting this, we observed enriched expression of NLGN1 in the ER, with decreased expression at the synapse. NLGN1 is necessary for synapse-organizing proteins, mediating cell adhesion and recruiting components to developing synapses, and dysregulation of its localization may have critical effects on these pathways in SCZ.

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© The Author 2017. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: [email protected]
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