Shared miRNA landscapes of COVID-19 and neurodegeneration confirm neuroinflammation as an important overlapping feature

Abstract

IntroductionDevelopment and worsening of most common neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis, have been associated with COVID-19 However, the mechanisms associated with neurological symptoms in COVID-19 patients and neurodegenerative sequelae are not clear. The interplay between gene expression and metabolite production in CNS is driven by miRNAs. These small non-coding molecules are dysregulated in most common neurodegenerative diseases and COVID-19.MethodsWe have performed a thorough literature screening and database mining to search for shared miRNA landscapes of SARS-CoV-2 infection and neurodegeneration. Differentially expressed miRNAs in COVID-19 patients were searched using PubMed, while differentially expressed miRNAs in patients with five most common neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and multiple sclerosis) were searched using the Human microRNA Disease Database. Target genes of the overlapping miRNAs, identified with the miRTarBase, were used for the pathway enrichment analysis performed with Kyoto Encyclopedia of Genes and Genomes and Reactome.ResultsIn total, 98 common miRNAs were found. Additionally, two of them (hsa-miR-34a and hsa-miR-132) were highlighted as promising biomarkers of neurodegeneration, as they are dysregulated in all five most common neurodegenerative diseases and COVID-19. Additionally, hsa-miR-155 was upregulated in four COVID-19 studies and found to be dysregulated in neurodegeneration processes as well. Screening for miRNA targets identified 746 unique genes with strong evidence for interaction. Target enrichment analysis highlighted most significant KEGG and Reactome pathways being involved in signaling, cancer, transcription and infection. However, the more specific identified pathways confirmed neuroinflammation as being the most important shared feature.DiscussionOur pathway based approach has identified overlapping miRNAs in COVID-19 and neurodegenerative diseases that may have a valuable potential for neurodegeneration prediction in COVID-19 patients. Additionally, identified miRNAs can be further explored as potential drug targets or agents to modify signaling in shared pathways.Graphical AbstractShared miRNA molecules among the five investigated neurodegenerative diseases and COVID-19 were identified. The two overlapping miRNAs, hsa-miR-34a and has-miR-132, present potential biomarkers of neurodegenerative sequelae after COVID-19. Furthermore, 98 common miRNAs between all five neurodegenerative diseases together and COVID-19 were identified. A KEGG and Reactome pathway enrichment analyses was performed on the list of shared miRNA target genes and finally top 20 pathways were evaluated for their potential for identification of new drug targets. A common feature of identified overlapping miRNAs and pathways is neuroinflammation. AD, Alzheimer’s disease; ALS, amyotrophic lateral sclerosis; COVID-19, coronavirus disease 2019; HD, Huntington’s disease; KEGG, Kyoto Encyclopedia of Genes and Genomes; MS, multiple sclerosis; PD, Parkinson’s disease.

MicroRNA (miRNA) Complexity in Alzheimer’s Disease (AD)

“…RNA-based medications can include stabilized miRNAs, anti-miRNA (AM, antagomir) and other approaches directed against specific miRNA activators such as NF-kB (p50/p65), using targeted anti-NF-kB (p50/p65) treatment strategies, or any combination of these advanced therapeutics. NV, EX and/or EMV packets containing strategically designed and stabilized miRNA, anti-miRNA (AM), mRNA in conjunction with other therapeutic components and inflammatory mediators and tailored to individual AD patients using precision medicine and predictive, participatory, preventive and personalized (P4) approaches should be useful in the clinical management of AD and other complex neurological disorders that are now urgently requiring effective disease-modifying intervention [ 17 , 35 , 53 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 75 , 79 , 80 , 81 , 82 , 100 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 ].…”

“…The intrinsic complexity and magnitude of gene expression in the human brain and CNS make the elucidation of even fundamental miRNA-mRNA signaling pathways exceptionally challenging, as does the search for reliable biomarkers for neurodegeneration in the periphery. The manipulation of gene expression using miRNA-based strategies and the use of extracellular vesicles for therapeutic delivery should be of great strategic value in the clinical management of AD and related forms of progressive age-related inflammatory neurodegeneration [ 31 , 35 , 50 , 51 , 80 , 81 , 82 , 83 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 ].…”

Mechanism and Therapeutic Prospect of miRNAs in Neurodegenerative Diseases

“…In PD, hsa-mir-129-2-3p is a brain-enriched miRNAs that are elevated in the patient's peripheral lymphocytes and most significantly associated with the hub gene. It is suggested that miRNAs may become a potential therapeutic target for infectious diseases such as SARS CoV-2, swine flu, influenza, and the complications of nervous system disease caused by them [ 213 , 214 ]. Although studies have found that specific miRNAs have excellent performance in the treatment and diagnosis of neurodegenerative disease, there are also some limitations.…”

Systems genetics identifies miRNA-mediated regulation of host response in COVID-19

“…Latini and colleagues showed a functional role for hsa-let7b-5p in modulating levels of ACE2 and DPP4—two receptors that play an important role in the onset and progression of COVID-19 disease—and established that low expression of this miRNA was associated with ACE2 and DPP4 overexpression in naso-oropharyngeal swabs in COVID-19 patients [ 40 ]. Meanwhile, seeking to better understand the mechanism behind neurological symptoms in COVID-19, Trampuž and colleagues highlighted 98 miRNAs that have been implicated in both COVID-19 and one of five neurological disorders [ 41 ]. Together, these studies implicate miRNAs in the human immune response to COVID-19 infection; however, most of them only included patient populations from Australia, Europe and North America, and none examined the effect of genome-wide genetic variation on host miRNA expression during SARS-CoV-2 infection.…”