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Evidence for abnormal forward trafficking of AMPA receptors in frontal cortex of elderly patients with schizophrenia.

ABSTRACT: Several lines of evidence point to alterations of alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor trafficking in schizophrenia. Multiple proteins, including synapse-associated protein 97 (SAP97), glutamate receptor-interacting protein 1 (GRIP1), and N-ethylmaleimide sensitive factor (NSF), facilitate the forward trafficking of AMPA receptors toward the synapse. Once localized to the synapse, AMPA receptors are trafficked in a complex endosomal system. We hypothesized that alterations in the expression of these proteins and alterations in the subcellular localization of AMPA receptors in endosomes may contribute to the pathophysiology of schizophrenia. Accordingly, we measured protein expression of SAP97, GRIP1, and NSF in the dorsolateral prefrontal cortex and found an increase in the expression of SAP97 and GRIP1 in schizophrenia. To determine the subcellular localization of AMPA receptor subunits, we developed a technique to isolate early endosomes from post-mortem tissue. We found increased GluR1 receptor subunit protein in early endosomes in subjects with schizophrenia. Together, these data suggest that there is an alteration of forward trafficking of AMPA receptors as well as changes in the subcellular localization of an AMPA receptor subunit in schizophrenia.

SUBMITTER: Hammond JC

PROVIDER: S-EPMC2922423 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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Evidence for abnormal forward trafficking of AMPA receptors in frontal cortex of elderly patients with schizophrenia.

Hammond John C JC McCullumsmith Robert E RE Funk Adam J AJ Haroutunian Vahram V Meador-Woodruff James H JH

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20100623 10

Several lines of evidence point to alterations of alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor trafficking in schizophrenia. Multiple proteins, including synapse-associated protein 97 (SAP97), glutamate receptor-interacting protein 1 (GRIP1), and N-ethylmaleimide sensitive factor (NSF), facilitate the forward trafficking of AMPA receptors toward the synapse. Once localized to the synapse, AMPA receptors are trafficked in a complex endosomal system. We hypothesized that ...[more]

PMID: 20571483

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Project description:Abnormalities of posttranslational protein modifications (PTMs) have recently been implicated in the pathophysiology of schizophrenia. Glycosylphosphatidylinositols (GPIs) are a class of complex glycolipids, which anchor surface proteins and glycoproteins to the cell membrane. GPI attachment to proteins represents one of the most common PTMs and GPI-associated proteins (GPI-APs) facilitate many cell surface processes, including synapse development and maintenance. Mutations in the GPI processing pathway are associated with intellectual disability, emphasizing the potential role of GPI-APs in cognition and schizophrenia-associated cognitive dysfunction. As initial endoplasmic reticulum (ER)-associated protein processing is essential for GPI-AP function, we measured protein expression of molecules involved in attachment (GPAA1), modification (PGAP1), and ER export (Tmp21) of GPI-APs, in homogenates and in an ER enriched fraction derived from dorsolateral prefrontal cortex (DLPFC) of 15 matched pairs of schizophrenia and comparison subjects. In total homogenate we found a significant decrease in transmembrane protein 21 (Tmp21) and in the ER-enriched fraction we found reduced expression of post-GPI attachment protein (PGAP1). PGAP1 modifies GPI-anchors through inositol deacylation, allowing it to be recognized by Tmp21. Tmp21 is a component of the p24 complex that recognizes GPI-anchored proteins, senses the status of the GPI-anchor, and regulates incorporation into COPII vesicles for export to the Golgi apparatus. Together, these proteins are the molecular mechanisms underlying GPI-AP quality control and ER export. To investigate the potential consequences of a deficit in export and/or quality control, we measured cell membrane-associated expression of known GPI-APs that have been previously implicated in schizophrenia, including GPC1, NCAM, MDGA2, and EPHA1, using Triton X-114 phase separation. Additionally, we tested the sensitivity of those candidate proteins to phosphatidylinositol-specific phospholipase C (PI-PLC), an enzyme that cleaves GPI from GPI-APs. While we did not observe a difference in the amount of these GPI-APs in Triton X-114 phase separated membrane fractions, we found decreased NCAM and GPC1 within the PI-PLC sensitive fraction. These findings suggest dysregulation of ER-associated GPI-AP protein processing, with impacts on post-translational modifications of proteins previously implicated in schizophrenia such as NCAM and GPC1. These findings provide evidence for a deficit in ER protein processing pathways in this illness.

Dataset Information

Evidence for abnormal forward trafficking of AMPA receptors in frontal cortex of elderly patients with schizophrenia.

Publications

Evidence for abnormal forward trafficking of AMPA receptors in frontal cortex of elderly patients with schizophrenia.

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