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Characterization of exogenous αSN response genes and their relation to Parkinson’s disease using network analyses
Despite extensive research, the molecular mechanisms underlying the toxicity of αSN in Parkinson’s disease (PD) pathology are still poorly understood. To address this, we used a microarray dataset to identify genes that are induced and differentially expressed after exposure to toxic αSN aggregates,...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9563388/ https://www.ncbi.nlm.nih.gov/pubmed/36249814 http://dx.doi.org/10.3389/fphar.2022.966760 |
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author | Nayeri, Zahra Aliakbari, Farhang Afzali, Farzaneh Parsafar, Soha Gharib, Ehsan Otzen, Daniel E. Morshedi, Dina |
author_facet | Nayeri, Zahra Aliakbari, Farhang Afzali, Farzaneh Parsafar, Soha Gharib, Ehsan Otzen, Daniel E. Morshedi, Dina |
author_sort | Nayeri, Zahra |
collection | PubMed |
description | Despite extensive research, the molecular mechanisms underlying the toxicity of αSN in Parkinson’s disease (PD) pathology are still poorly understood. To address this, we used a microarray dataset to identify genes that are induced and differentially expressed after exposure to toxic αSN aggregates, which we call exogenous αSN response (EASR) genes. Using systems biology approaches, we then determined, at multiple levels of analysis, how these EASR genes could be related to PD pathology. A key result was the identification of functional connections between EASR genes and previously identified PD-related genes by employing the proteins’ interactions networks and 9 brain region-specific co-expression networks. In each brain region, co-expression modules of EASR genes were enriched for gene sets whose expression are altered by SARS-CoV-2 infection, leading to the hypothesis that EASR co-expression genes may explain the observed links between COVID-19 and PD. An examination of the expression pattern of EASR genes in different non-neurological healthy brain regions revealed that regions with lower mean expression of the upregulated EASR genes, such as substantia nigra, are more vulnerable to αSN aggregates and lose their neurological functions during PD progression. Gene Set Enrichment Analysis of healthy and PD samples from substantia nigra revealed that a specific co-expression network, “TNF-α signaling via NF-κB”, is an upregulated pathway associated with the PD phenotype. Inhibitors of the “TNF-α signaling via NF-κB” pathway may, therefore, decrease the activity level of this pathway and thereby provide therapeutic benefits for PD patients. We virtually screened FDA-approved drugs against these upregulated genes (NR4A1, DUSP1, and FOS) using docking-based drug discovery and identified several promising drugs. Altogether, our study provides a better understanding of αSN toxicity mechanisms in PD and identifies potential therapeutic targets and small molecules for treatment of PD. |
format | Online Article Text |
id | pubmed-9563388 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-95633882022-10-15 Characterization of exogenous αSN response genes and their relation to Parkinson’s disease using network analyses Nayeri, Zahra Aliakbari, Farhang Afzali, Farzaneh Parsafar, Soha Gharib, Ehsan Otzen, Daniel E. Morshedi, Dina Front Pharmacol Pharmacology Despite extensive research, the molecular mechanisms underlying the toxicity of αSN in Parkinson’s disease (PD) pathology are still poorly understood. To address this, we used a microarray dataset to identify genes that are induced and differentially expressed after exposure to toxic αSN aggregates, which we call exogenous αSN response (EASR) genes. Using systems biology approaches, we then determined, at multiple levels of analysis, how these EASR genes could be related to PD pathology. A key result was the identification of functional connections between EASR genes and previously identified PD-related genes by employing the proteins’ interactions networks and 9 brain region-specific co-expression networks. In each brain region, co-expression modules of EASR genes were enriched for gene sets whose expression are altered by SARS-CoV-2 infection, leading to the hypothesis that EASR co-expression genes may explain the observed links between COVID-19 and PD. An examination of the expression pattern of EASR genes in different non-neurological healthy brain regions revealed that regions with lower mean expression of the upregulated EASR genes, such as substantia nigra, are more vulnerable to αSN aggregates and lose their neurological functions during PD progression. Gene Set Enrichment Analysis of healthy and PD samples from substantia nigra revealed that a specific co-expression network, “TNF-α signaling via NF-κB”, is an upregulated pathway associated with the PD phenotype. Inhibitors of the “TNF-α signaling via NF-κB” pathway may, therefore, decrease the activity level of this pathway and thereby provide therapeutic benefits for PD patients. We virtually screened FDA-approved drugs against these upregulated genes (NR4A1, DUSP1, and FOS) using docking-based drug discovery and identified several promising drugs. Altogether, our study provides a better understanding of αSN toxicity mechanisms in PD and identifies potential therapeutic targets and small molecules for treatment of PD. Frontiers Media S.A. 2022-09-30 /pmc/articles/PMC9563388/ /pubmed/36249814 http://dx.doi.org/10.3389/fphar.2022.966760 Text en Copyright © 2022 Nayeri, Aliakbari, Afzali, Parsafar, Gharib, Otzen and Morshedi. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology Nayeri, Zahra Aliakbari, Farhang Afzali, Farzaneh Parsafar, Soha Gharib, Ehsan Otzen, Daniel E. Morshedi, Dina Characterization of exogenous αSN response genes and their relation to Parkinson’s disease using network analyses |
title | Characterization of exogenous αSN response genes and their relation to Parkinson’s disease using network analyses |
title_full | Characterization of exogenous αSN response genes and their relation to Parkinson’s disease using network analyses |
title_fullStr | Characterization of exogenous αSN response genes and their relation to Parkinson’s disease using network analyses |
title_full_unstemmed | Characterization of exogenous αSN response genes and their relation to Parkinson’s disease using network analyses |
title_short | Characterization of exogenous αSN response genes and their relation to Parkinson’s disease using network analyses |
title_sort | characterization of exogenous αsn response genes and their relation to parkinson’s disease using network analyses |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9563388/ https://www.ncbi.nlm.nih.gov/pubmed/36249814 http://dx.doi.org/10.3389/fphar.2022.966760 |
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