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Protein expression of prenyltransferase subunits in postmortem schizophrenia dorsolateral prefrontal cortex

The pathophysiology of schizophrenia includes altered neurotransmission, dysregulated intracellular signaling pathway activity, and abnormal dendritic morphology that contribute to deficits of synaptic plasticity in the disorder. These processes all require dynamic protein–protein interactions at ce...

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Autores principales: Pinner, Anita L., Mueller, Toni M., Alganem, Khaled, McCullumsmith, Robert, Meador-Woodruff, James H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026430/
https://www.ncbi.nlm.nih.gov/pubmed/32066669
http://dx.doi.org/10.1038/s41398-019-0610-7
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author Pinner, Anita L.
Mueller, Toni M.
Alganem, Khaled
McCullumsmith, Robert
Meador-Woodruff, James H.
author_facet Pinner, Anita L.
Mueller, Toni M.
Alganem, Khaled
McCullumsmith, Robert
Meador-Woodruff, James H.
author_sort Pinner, Anita L.
collection PubMed
description The pathophysiology of schizophrenia includes altered neurotransmission, dysregulated intracellular signaling pathway activity, and abnormal dendritic morphology that contribute to deficits of synaptic plasticity in the disorder. These processes all require dynamic protein–protein interactions at cell membranes. Lipid modifications target proteins to membranes by increasing substrate hydrophobicity by the addition of a fatty acid or isoprenyl moiety, and recent evidence suggests that dysregulated posttranslational lipid modifications may play a role in multiple neuropsychiatric disorders, including schizophrenia. Consistent with these emerging findings, we have recently reported decreased protein S-palmitoylation in schizophrenia. Protein prenylation is a lipid modification that occurs upstream of S-palmitoylation on many protein substrates, facilitating membrane localization and activity of key intracellular signaling proteins. Accordingly, we hypothesized that, in addition to palmitoylation, protein prenylation may be abnormal in schizophrenia. To test this, we assayed protein expression of the five prenyltransferase subunits (FNTA, FNTB, PGGT1B, RABGGTA, and RABGGTB) in postmortem dorsolateral prefrontal cortex from patients with schizophrenia and paired comparison subjects (n = 13 pairs). We found decreased levels of FNTA (14%), PGGT1B (13%), and RABGGTB (8%) in schizophrenia. To determine whether upstream or downstream factors may be driving these changes, we also assayed protein expression of the isoprenoid synthases FDPS and GGPS1 and prenylation-dependent processing enzymes RCE and ICMT. We found these upstream and downstream enzymes to have normal protein expression. To rule out effects from chronic antipsychotic treatment, we assayed FNTA, PGGT1B, and RABGGTB in the cortex from rats treated long-term with haloperidol decanoate and found no change in the expression of these proteins. Given the role prenylation plays in localization of key signaling proteins found at the synapse, these data offer a potential mechanism underlying abnormal protein–protein interactions and protein localization in schizophrenia.
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spelling pubmed-70264302020-03-03 Protein expression of prenyltransferase subunits in postmortem schizophrenia dorsolateral prefrontal cortex Pinner, Anita L. Mueller, Toni M. Alganem, Khaled McCullumsmith, Robert Meador-Woodruff, James H. Transl Psychiatry Article The pathophysiology of schizophrenia includes altered neurotransmission, dysregulated intracellular signaling pathway activity, and abnormal dendritic morphology that contribute to deficits of synaptic plasticity in the disorder. These processes all require dynamic protein–protein interactions at cell membranes. Lipid modifications target proteins to membranes by increasing substrate hydrophobicity by the addition of a fatty acid or isoprenyl moiety, and recent evidence suggests that dysregulated posttranslational lipid modifications may play a role in multiple neuropsychiatric disorders, including schizophrenia. Consistent with these emerging findings, we have recently reported decreased protein S-palmitoylation in schizophrenia. Protein prenylation is a lipid modification that occurs upstream of S-palmitoylation on many protein substrates, facilitating membrane localization and activity of key intracellular signaling proteins. Accordingly, we hypothesized that, in addition to palmitoylation, protein prenylation may be abnormal in schizophrenia. To test this, we assayed protein expression of the five prenyltransferase subunits (FNTA, FNTB, PGGT1B, RABGGTA, and RABGGTB) in postmortem dorsolateral prefrontal cortex from patients with schizophrenia and paired comparison subjects (n = 13 pairs). We found decreased levels of FNTA (14%), PGGT1B (13%), and RABGGTB (8%) in schizophrenia. To determine whether upstream or downstream factors may be driving these changes, we also assayed protein expression of the isoprenoid synthases FDPS and GGPS1 and prenylation-dependent processing enzymes RCE and ICMT. We found these upstream and downstream enzymes to have normal protein expression. To rule out effects from chronic antipsychotic treatment, we assayed FNTA, PGGT1B, and RABGGTB in the cortex from rats treated long-term with haloperidol decanoate and found no change in the expression of these proteins. Given the role prenylation plays in localization of key signaling proteins found at the synapse, these data offer a potential mechanism underlying abnormal protein–protein interactions and protein localization in schizophrenia. Nature Publishing Group UK 2020-01-10 /pmc/articles/PMC7026430/ /pubmed/32066669 http://dx.doi.org/10.1038/s41398-019-0610-7 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Pinner, Anita L.
Mueller, Toni M.
Alganem, Khaled
McCullumsmith, Robert
Meador-Woodruff, James H.
Protein expression of prenyltransferase subunits in postmortem schizophrenia dorsolateral prefrontal cortex
title Protein expression of prenyltransferase subunits in postmortem schizophrenia dorsolateral prefrontal cortex
title_full Protein expression of prenyltransferase subunits in postmortem schizophrenia dorsolateral prefrontal cortex
title_fullStr Protein expression of prenyltransferase subunits in postmortem schizophrenia dorsolateral prefrontal cortex
title_full_unstemmed Protein expression of prenyltransferase subunits in postmortem schizophrenia dorsolateral prefrontal cortex
title_short Protein expression of prenyltransferase subunits in postmortem schizophrenia dorsolateral prefrontal cortex
title_sort protein expression of prenyltransferase subunits in postmortem schizophrenia dorsolateral prefrontal cortex
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026430/
https://www.ncbi.nlm.nih.gov/pubmed/32066669
http://dx.doi.org/10.1038/s41398-019-0610-7
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