ER stress in COVID-19 and Parkinson's Disease: in vitro and in silico evidences

Abstract

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.