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Deregulation of complement components C4A and CSMD1 peripheral expression in first-episode psychosis and links to cognitive ability

Up-regulation of the complement component 4A (C4A) in the brain has been associated with excessive synaptic pruning and increased schizophrenia (SZ) susceptibility. Over-expression of C4A has been observed in SZ postmortem brain tissue, and the gene encoding for a protein inhibitor of C4A activity,...

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Autores principales: Hatzimanolis, Alex, Foteli, Stefania, Stefanatou, Pentagiotissa, Ntigrintaki, Angeliki-Aikaterini, Ralli, Irene, Kollias, Konstantinos, Nikolaou, Chrysoula, Gazouli, Maria, Stefanis, Nikos C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9508018/
https://www.ncbi.nlm.nih.gov/pubmed/35532796
http://dx.doi.org/10.1007/s00406-022-01409-5
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author Hatzimanolis, Alex
Foteli, Stefania
Stefanatou, Pentagiotissa
Ntigrintaki, Angeliki-Aikaterini
Ralli, Irene
Kollias, Konstantinos
Nikolaou, Chrysoula
Gazouli, Maria
Stefanis, Nikos C.
author_facet Hatzimanolis, Alex
Foteli, Stefania
Stefanatou, Pentagiotissa
Ntigrintaki, Angeliki-Aikaterini
Ralli, Irene
Kollias, Konstantinos
Nikolaou, Chrysoula
Gazouli, Maria
Stefanis, Nikos C.
author_sort Hatzimanolis, Alex
collection PubMed
description Up-regulation of the complement component 4A (C4A) in the brain has been associated with excessive synaptic pruning and increased schizophrenia (SZ) susceptibility. Over-expression of C4A has been observed in SZ postmortem brain tissue, and the gene encoding for a protein inhibitor of C4A activity, CUB and Sushi multiple domains 1 (CSMD1) gene, has been implicated in SZ risk and cognitive ability. Herein, we examined C4A and CSMD1 mRNA expression in peripheral blood from antipsychotic-naive individuals with first-episode psychosis (FEP; n = 73) and mentally healthy volunteers (n = 48). Imputed C4 locus structural alleles and C4A serum protein levels were investigated. Associations with symptom severity and cognitive domains performance were explored. A significant decrease in CSMD1 expression levels was noted among FEP patients compared to healthy volunteers, further indicating a positive correlation between C4A and CSMD1 mRNA levels in healthy volunteers but not in FEP cases. In addition, C4 copy number variants previously associated with SZ risk correlated with higher C4A mRNA levels in FEP cases, which confirms the regulatory effect of C4 structural variants on gene expression. Evidence also emerged for markedly elevated C4A serum concentrations in FEP cases. Within the FEP patient group, higher C4A mRNA levels correlated with more severe general psychopathology symptoms and lower CSMD1 mRNA levels predicted worse working memory performance. Overall, these findings suggest C4A complement pathway perturbations in individuals with FEP and corroborate the involvement of CSMD1 in prefrontal-mediated cognitive functioning. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00406-022-01409-5.
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spelling pubmed-95080182022-09-25 Deregulation of complement components C4A and CSMD1 peripheral expression in first-episode psychosis and links to cognitive ability Hatzimanolis, Alex Foteli, Stefania Stefanatou, Pentagiotissa Ntigrintaki, Angeliki-Aikaterini Ralli, Irene Kollias, Konstantinos Nikolaou, Chrysoula Gazouli, Maria Stefanis, Nikos C. Eur Arch Psychiatry Clin Neurosci Original Paper Up-regulation of the complement component 4A (C4A) in the brain has been associated with excessive synaptic pruning and increased schizophrenia (SZ) susceptibility. Over-expression of C4A has been observed in SZ postmortem brain tissue, and the gene encoding for a protein inhibitor of C4A activity, CUB and Sushi multiple domains 1 (CSMD1) gene, has been implicated in SZ risk and cognitive ability. Herein, we examined C4A and CSMD1 mRNA expression in peripheral blood from antipsychotic-naive individuals with first-episode psychosis (FEP; n = 73) and mentally healthy volunteers (n = 48). Imputed C4 locus structural alleles and C4A serum protein levels were investigated. Associations with symptom severity and cognitive domains performance were explored. A significant decrease in CSMD1 expression levels was noted among FEP patients compared to healthy volunteers, further indicating a positive correlation between C4A and CSMD1 mRNA levels in healthy volunteers but not in FEP cases. In addition, C4 copy number variants previously associated with SZ risk correlated with higher C4A mRNA levels in FEP cases, which confirms the regulatory effect of C4 structural variants on gene expression. Evidence also emerged for markedly elevated C4A serum concentrations in FEP cases. Within the FEP patient group, higher C4A mRNA levels correlated with more severe general psychopathology symptoms and lower CSMD1 mRNA levels predicted worse working memory performance. Overall, these findings suggest C4A complement pathway perturbations in individuals with FEP and corroborate the involvement of CSMD1 in prefrontal-mediated cognitive functioning. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00406-022-01409-5. Springer Berlin Heidelberg 2022-05-09 2022 /pmc/articles/PMC9508018/ /pubmed/35532796 http://dx.doi.org/10.1007/s00406-022-01409-5 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Paper
Hatzimanolis, Alex
Foteli, Stefania
Stefanatou, Pentagiotissa
Ntigrintaki, Angeliki-Aikaterini
Ralli, Irene
Kollias, Konstantinos
Nikolaou, Chrysoula
Gazouli, Maria
Stefanis, Nikos C.
Deregulation of complement components C4A and CSMD1 peripheral expression in first-episode psychosis and links to cognitive ability
title Deregulation of complement components C4A and CSMD1 peripheral expression in first-episode psychosis and links to cognitive ability
title_full Deregulation of complement components C4A and CSMD1 peripheral expression in first-episode psychosis and links to cognitive ability
title_fullStr Deregulation of complement components C4A and CSMD1 peripheral expression in first-episode psychosis and links to cognitive ability
title_full_unstemmed Deregulation of complement components C4A and CSMD1 peripheral expression in first-episode psychosis and links to cognitive ability
title_short Deregulation of complement components C4A and CSMD1 peripheral expression in first-episode psychosis and links to cognitive ability
title_sort deregulation of complement components c4a and csmd1 peripheral expression in first-episode psychosis and links to cognitive ability
topic Original Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9508018/
https://www.ncbi.nlm.nih.gov/pubmed/35532796
http://dx.doi.org/10.1007/s00406-022-01409-5
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