Characterization of exogenous αSN response genes and their relation to Parkinson's disease using network analyses

TY - JOUR

T1 - Characterization of exogenous αSN response genes and their relation to Parkinson's disease using network analyses

AU - Nayeri, Zahra

AU - Aliakbari, Farhang

AU - Afzali, Farzaneh

AU - Parsafar, Soha

AU - Gharib, Ehsan

AU - Otzen, Daniel E

AU - Morshedi, Dina

N1 - Copyright © 2022 Nayeri, Aliakbari, Afzali, Parsafar, Gharib, Otzen and Morshedi.

PY - 2022

Y1 - 2022

N2 - 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.

AB - 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.

KW - COVID-19

KW - Parkinsion’s disease

KW - entrectinib

KW - irinotecan

KW - systems biology

KW - α-synuclein

UR - http://www.scopus.com/inward/record.url?scp=85140975620&partnerID=8YFLogxK

U2 - 10.3389/fphar.2022.966760

DO - 10.3389/fphar.2022.966760

M3 - Journal article

C2 - 36249814

SN - 1663-9812

VL - 13

JO - Frontiers in Pharmacology

JF - Frontiers in Pharmacology

M1 - 966760

ER -