ER Stress in COVID-19 and Parkinson’s Disease: In Vitro and In Silico Evidences
The outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) signifies a serious worldwide concern to public health. Both transcriptome and proteome of SARS-CoV-2-infected cells synergize the progression of infection in host, which may exacerbate symptoms and/or pr...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-04-01
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| Series: | Brain Sciences |
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| Online Access: | https://www.mdpi.com/2076-3425/12/4/507 |
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| author | Zahara L. Chaudhry Mahmoud Gamal Ingrid Ferhati Mohamad Warda Bushra Y. Ahmed |
| author_facet | Zahara L. Chaudhry Mahmoud Gamal Ingrid Ferhati Mohamad Warda Bushra Y. Ahmed |
| author_sort | Zahara L. Chaudhry |
| collection | DOAJ |
| description | The outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) signifies a serious worldwide concern to public health. Both transcriptome and proteome of SARS-CoV-2-infected cells synergize the progression of infection in host, which may exacerbate symptoms and/or progression of other chronic diseases such as Parkinson’s disease (PD). Oxidative stress is a well-known cause of endoplasmic reticulum (ER) stress observed in both SARS-CoV-2 and PD. In the current study, we aimed to explore the influence of PKR-like ER kinase (PERK) stress pathway under SARS-CoV-2-mediated infection and in human cell model of PD. Furthermore, we investigated whether they are interconnected and if the ER stress inhibitors could inhibit cell death and provide cellular protection. To achieve this aim, we have incorporated in silico analysis obtained from gene set enrichment analysis (GSEA), a literature review and laboratory data. The neurotoxin, 6-hydroxy dopamine (6OHDA), was used to mimic the biochemical and neuropathological characteristics of PD by inducing oxidative stress in dopamine-containing neurons differentiated from ReNVM cell line (dDCNs). Furthermore, we explored if ER stress influences activation of caspases-2, -4 and -8 in SARS-CoV-2 and in stressed dDCNs. Our laboratory data using Western blot, immunocytochemistry and 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) analyses indicated that 6OHDA-induced toxicity triggered activation of caspases-2, -4 and -8 in dDCNs. Under SARS-CoV-2 infection of different cell types, GSEA revealed cell-specific sensitivities to oxidative and ER stresses. Cardiomyocytes and type II alveolar epithelial-like cells were more vulnerable to oxidative stress than neural cells. On the other side, only cardiomyocytes activated the unfolded protein response, however, the PERK pathway was operative in both cardiomyocytes and neural cells. In addition, caspase-4 activation by a SARS-CoV-2 was observed via in silico analyses. These results demonstrate that the ER stress pathway under oxidative stress in SARS-CoV-2 and PD are interconnected using diverse pathways. Furthermore, our results using the ER stress inhibitor and caspase specific inhibitors provided cellular protection suggesting that the use of specific inhibitors can provide effective therapeutic approaches for the treatment of COVID-19 and PD. |
| first_indexed | 2024-03-09T11:04:55Z |
| format | Article |
| id | doaj.art-2d27bc3d2a9b48fbb7e9f9d58e0d0b34 |
| institution | Directory Open Access Journal |
| issn | 2076-3425 |
| language | English |
| last_indexed | 2024-03-09T11:04:55Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Brain Sciences |
| spelling | doaj.art-2d27bc3d2a9b48fbb7e9f9d58e0d0b342023-12-01T01:00:29ZengMDPI AGBrain Sciences2076-34252022-04-0112450710.3390/brainsci12040507ER Stress in COVID-19 and Parkinson’s Disease: In Vitro and In Silico EvidencesZahara L. Chaudhry0Mahmoud Gamal1Ingrid Ferhati2Mohamad Warda3Bushra Y. Ahmed4Institute of Biomedical & Environmental Science and Technology, School of Life Sciences, Faculty of Creative Arts, Technologies & Science, University Square, University of Bedfordshire, Luton LU1 3JU, UKDepartment of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Cairo University, Giza 12211, EgyptInstitute of Biomedical & Environmental Science and Technology, School of Life Sciences, Faculty of Creative Arts, Technologies & Science, University Square, University of Bedfordshire, Luton LU1 3JU, UKDepartment of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Cairo University, Giza 12211, EgyptInstitute of Biomedical & Environmental Science and Technology, School of Life Sciences, Faculty of Creative Arts, Technologies & Science, University Square, University of Bedfordshire, Luton LU1 3JU, UKThe outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) signifies a serious worldwide concern to public health. Both transcriptome and proteome of SARS-CoV-2-infected cells synergize the progression of infection in host, which may exacerbate symptoms and/or progression of other chronic diseases such as Parkinson’s disease (PD). Oxidative stress is a well-known cause of endoplasmic reticulum (ER) stress observed in both SARS-CoV-2 and PD. In the current study, we aimed to explore the influence of PKR-like ER kinase (PERK) stress pathway under SARS-CoV-2-mediated infection and in human cell model of PD. Furthermore, we investigated whether they are interconnected and if the ER stress inhibitors could inhibit cell death and provide cellular protection. To achieve this aim, we have incorporated in silico analysis obtained from gene set enrichment analysis (GSEA), a literature review and laboratory data. The neurotoxin, 6-hydroxy dopamine (6OHDA), was used to mimic the biochemical and neuropathological characteristics of PD by inducing oxidative stress in dopamine-containing neurons differentiated from ReNVM cell line (dDCNs). Furthermore, we explored if ER stress influences activation of caspases-2, -4 and -8 in SARS-CoV-2 and in stressed dDCNs. Our laboratory data using Western blot, immunocytochemistry and 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) analyses indicated that 6OHDA-induced toxicity triggered activation of caspases-2, -4 and -8 in dDCNs. Under SARS-CoV-2 infection of different cell types, GSEA revealed cell-specific sensitivities to oxidative and ER stresses. Cardiomyocytes and type II alveolar epithelial-like cells were more vulnerable to oxidative stress than neural cells. On the other side, only cardiomyocytes activated the unfolded protein response, however, the PERK pathway was operative in both cardiomyocytes and neural cells. In addition, caspase-4 activation by a SARS-CoV-2 was observed via in silico analyses. These results demonstrate that the ER stress pathway under oxidative stress in SARS-CoV-2 and PD are interconnected using diverse pathways. Furthermore, our results using the ER stress inhibitor and caspase specific inhibitors provided cellular protection suggesting that the use of specific inhibitors can provide effective therapeutic approaches for the treatment of COVID-19 and PD.https://www.mdpi.com/2076-3425/12/4/507Parkinson’s diseaseSARS-CoV-2caspaseendoplasmic reticulum (ER) stressPKR-like ER kinase (PERK)6OHDA |
| spellingShingle | Zahara L. Chaudhry Mahmoud Gamal Ingrid Ferhati Mohamad Warda Bushra Y. Ahmed ER Stress in COVID-19 and Parkinson’s Disease: In Vitro and In Silico Evidences Brain Sciences Parkinson’s disease SARS-CoV-2 caspase endoplasmic reticulum (ER) stress PKR-like ER kinase (PERK) 6OHDA |
| title | ER Stress in COVID-19 and Parkinson’s Disease: In Vitro and In Silico Evidences |
| title_full | ER Stress in COVID-19 and Parkinson’s Disease: In Vitro and In Silico Evidences |
| title_fullStr | ER Stress in COVID-19 and Parkinson’s Disease: In Vitro and In Silico Evidences |
| title_full_unstemmed | ER Stress in COVID-19 and Parkinson’s Disease: In Vitro and In Silico Evidences |
| title_short | ER Stress in COVID-19 and Parkinson’s Disease: In Vitro and In Silico Evidences |
| title_sort | er stress in covid 19 and parkinson s disease in vitro and in silico evidences |
| topic | Parkinson’s disease SARS-CoV-2 caspase endoplasmic reticulum (ER) stress PKR-like ER kinase (PERK) 6OHDA |
| url | https://www.mdpi.com/2076-3425/12/4/507 |
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