The COVID19 outbreak has undoubtedly become an international concern (2021). Some case reports hypothesized rapid onset of PD happens after SARS-CoV-2 infection (Cartella et al. 2021; Merello et al. 2021). However, there is no study aimed to investigate common links between covid-19 and PD yet in an in-silico manner.
In this study, we adopted a network-based approach following transcriptome analysis to detect the common molecular pathways involved in COVID-19 and PD pathogenesis. The analysis demonstrated 81 common DEGs between COVID-19 and PD. We then performed the pathway enrichment analysis of common DEG. Our results showed the complement and coagulation cascades are one of the pathways that are enriched by the common DEGs. The complement system plays a double role in the immune response against SARS-CoV-2 and the pathogenesis of COVID-19 tissue involvement (Gao et al. 2020; Diao et al. 2021). Several studies reported complement components to alter within the blood of PD patients (Goldknopf et al. 2006). The type II interferon signaling (IFNG) pathway was also identified. The interferon (IFN) responses constitute the main first line of defense against SARS-CoV-2 (Park and Iwasaki 2020). IFN-γ has a role in inflammation and neurodegeneration in PD, as an increase of IFN-γ was detected in the serum of PD patients (Baba et al. 2005). Another common pathway was oxidative damage. Oxidative stress most likely impacts COVID-19 pathogenesis by accompanying cell activation (Chernyak et al. 2020). Oxidative stress is one of the mechanisms mentioned in the etiopathogenesis of PD (Dorszewska et al. 2021). Oxidative stress causes damage to key cellular components in the substantia nigra (SN) of PD patients (Dias et al. 2013). We detected microglia pathogen phagocytosis pathway in which microglia by some pathogenic mechanisms, could contribute to the development of post-COVID-19 neurological sequelae and disorders, including PD (Awogbindin et al. 2021). Another enriched pathway was GABAergic synapse. COVID-19-associated inflammation may induce a cortical impairment of GABAergic neurotransmission, possibly representing cognitive fatigue, apathy, and executive deficits (Ortelli et al. 2021). GABA has also been reported to be involved in neurodegenerative disorders such as PD (Muñoz et al. 2020).
The hub genes have been identified from the PPIN to detect major signaling elements that may be used as therapeutic targets for the development of novel drugs to treat COVID-19 patients with PD comorbidity. MX1 is one of the myxovirus resistance genes (MX) which has the antiviral effect against RNA viruses. MX1 expression has been reported to be elevated in COVID-19 patients and conversely decline as age increases. Plus, it can be stimulated in the cytoplasm by IFNs and participates in the cellular antiviral response to SARS-COV-2 (Bizzotto et al. 2020). Furthermore, the accumulation of α-synuclein (α-SYN) in the brain of PD patients induces the expression of MX1. This molecule is involved in PI3K-Akt signaling pathway, cytokine release, immune response IFNs α, β, and γ signaling pathways (Yamada et al. 1994; Qin et al. 2016). It is also a regulator of IFN systems that contributes to CS (Yang et al. 2021). This might facilitate the entry of virus to CNS via BBB. It is noteworthy that BBB was reported to be disrupted in the animal models of PD which can lead to degeneration of neurons in substantia nigra (Al-Bachari et al. 2020). MX1 localized in self-aggregations and generated Lewy bodies and swelling of neuronal processes in the substantia nigra of brain tissues in Parkinson's patients (McDonough et al. 2017). Lewy bodies which contain misfolded proteins can then trigger activation of T-cells (Sulzer et al. 2017). IFN-alpha inducible (IRI) family members are closely related to the inflammatory immune response in COVID-19 and PD (Shaath et al. 2020). IFI6 is an Immune-associated early predictor for PD (Lei et al. 2020; Yu et al. 2020). IFI35 involved in Type I interferon signaling pathway and have a vital role in inflammation response in SARS-CoV-2 infected cells (Hachim et al. 2020; Ziegler et al. 2020; Ong et al. 2021). On the other hand, IFI35 upregulated in PD patients in response to INFs response (Yu et al. 2020). IFI35 gene is expressed in the stratum and substantia nigra regions of brain and its de novo mutation is contributed to early-onset of PD pathogenesis (Guo et al. 2018). IFI27 is an early predictor for SARS-COV-2 infection and high-level expression of IF127 is associated with the presence of a high viral load (Shojaei et al. 2021). One study found elevated expression of IFI27 after microglial activation and neuroinflammation in progressive neurodegenerative disorders such as PD (Zhou et al. 2015). SARS-CoV-2 infection induces a strong activation of major constituents of the human complement subcomponent C1q (C1QA, C1QB, C1QC) (Ramlall et al. 2020; Santiesteban-Lores et al. 2021). These genes are upregulated in the microglia cells in the brain of PD patients. Activation of the complement system improves the removal of pathogens and products of tissue damage from the brain and is related to neuronal cell death in PD (Depboylu et al. 2011; Mariani et al. 2016; Itoh and Voskuhl 2017). ELANE gene codes destructive enzymes named neutrophil elastase that play key role in host defense mechanism. This enzyme is highly overexpressed in naso-oropharyngeal and blood samples of COVID-19 patients. Neutrophil elastase can activate the spike (S) protein and mediate viral entry and pathogenesis of SARS-COV-2 (Belouzard et al. 2010; Akgun et al. 2020; Guéant et al. 2021). After an inflammatory insult to the CNS structure, the expression of neutrophil elastase increases, then degrades basal lamina and extracellular matrix (ECM) molecules, and suppress neurobehavioral recovery mechanisms (Stowe et al. 2009; Stock et al. 2018). Neutrophil Elastase Inhibitors could be new treatment options for COVID-19 patients (Mohamed et al. 2020).
Among these transcription factors, sex-determining region Y-box 2 (SOX2) has a critical role in the development and maintenance of neural stem/progenitor cell populations committed to becoming glial cells. SOX2 inhibits myelination in the peripheral nerves and maintains Schwann cells in a proliferative state, which is also associated with the influx of macrophages and increased neuroinflammation (Roberts et al. 2017). Interestingly, the expression level of SOX2 was found be elevated in the brains of PD patients (Vedam-Mai et al. 2014). Nerve inflammation is one of the important factors in the onset or progression of PD (Pajares et al. 2020). XAF1 is a mitochondrial apoptosis activator that is upregulated in immune cells (T, B, natural killer, and dendritic cells) of COVID-19 patients that may be associated with increased apoptosis of these cells (Zhu et al. 2020; Gao et al. 2021). Furthermore, XAF1 expression is higher in the midbrain of PD patients (Gispert et al. 2015; Santiago and Potashkin 2017). IFN-α and IFN-β induced XAF1 mRNA expression and therefore induced cell apoptosis (Leaman et al. 2002). The expression of Runt-related transcription factor 1 (RUNX1) increases after SARS-CoV-2 infection (O’Hare et al. 2021). Interestingly, its overexpression is related to the progression of PD. RUNX1 increases the expression of leucine-rich repeat kinase 2 (Lrrk2) gene in immune cells and has a critical role in the pathogenesis of familial PD due to developing hyperactive inflammatory phenotype, neuronal toxicity, and cell apoptosis (Cook et al. 2017; Thomsen et al. 2021). Microphthalmia-associated transcription factor (MITF) is one of the key TFs with varying functions in cell homeostasis, cell cycle, and apoptosis. MITF is upregulated in immune cells and worsens severity of infection in an unknown way in COVID-19 patients (Bost et al. 2020; Ding et al. 2021; Jeong et al. 2021). Ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) is expressed in neural cells and inhibits the stability of MITF by binding to the ubiquitinated protein. The ligase activity of UCHL1 is disrupted in PD, resulting in MITF overexpression and cell damage in these patients (Liu et al. 2002; Seo et al. 2017). The E26 transformation-specific (ETS) family transcription factor SPI1 upregulated in PBMCs of COVID-19 patients and is involved in the inflammatory process and modulates host immune systems of these patients (Fagone et al. 2020; Rahman et al. 2021). SPI1 plays a key role in the identity, differentiation, and specialized functions of microglia. Microglia rapidly activates in response to proinflammatory response. These activated microglia are accumulated in brain lesions of PD patients. SPI1 has many target functional genes in microglial cells including Spi1, Runx1, Irf8, Il34, Aif1, Csf1r, Csf1, Cx3cr1, Tyrobp, and Trem2 (Satoh et al. 2014). SPI1 induces cytokine release and microglial pro-inflammatory response (Pimenova et al. 2021). Therefore, misregulation of SPI1 target genes might lead to the establishment or development of PD due to the accumulation of activated microglia (Satoh et al. 2014). In addition, one multi-omic study identifies a Single-Nucleotide Polymorphism, rs10130373, within a microglia-specific peak, interrupts a SPI1 motif, and interfaces effectively with the promoter of the Rab interactor 3 (RIN3) gene. RIN3 plays an important role in the early endocytic pathway that needs microglial function, thereby, has a particularly critical role in progressive neurodegenerative disease (Kajiho et al. 2003; Corces et al. 2020).
hsa-mir-129-2-3p is the most significant miRNA in miRNA-Hub gene regulatory networks. miR-129 is a brain-enriched miRNA and its level increases in the peripheral blood lymphocytes of PD patients (Qin et al. 2016).
In the present study, an integrated bioinformatics approach was adopted to explore the possible risk of PD development after COVID-19 infection by investigating the common molecular mechanisms. By taking advantage of the holistic viewpoint of systems biology, we were able to consider every aspect of both diseases and infer novel hypotheses. Further supplementary studies need to be conducted to clarify the association between COVID-19 and PD, as at the moment, there is little known regarding both of these disease entities. It is worth mentioning that contracting PD is a complex and age-dependent neurodegenerative disorder. Thus, it is encouraged to investigate infected COVID-19 patients’ years after their infection to estimate the probability of getting PD.