September 18, 2020
Keio University School of Medicine
Assistant Professor Yoshitaka Kase and Professor Hideyuki Okano of the Department of Physiology, Keio University School of Medicine, have discovered that a molecule called CCN1 (Cyr61) may be involved as a pathogenic regulatory factor in central nervous system disorders caused by COVID-19.
While it is known that COVID-19 can cause not only pneumonia but also central nervous system disorders, the underlying mechanism has not been well understood. In this study, we first conducted a database analysis and found that the expression levels of ACE2, the receptor for SARS-CoV-2, and CCN1 were high in the lesions of encephalopathy caused by COVID-19. Although cases of meningitis due to COVID-19 have been reported where SARS-CoV-2 was detected only in the cerebrospinal fluid, our analysis of existing central nervous system databases revealed that the expression levels of ACE2 and CCN1 were also high in the choroid plexus, which produces the cerebrospinal fluid involved in these cases. Furthermore, a reanalysis of previously reported COVID-19 studies showed that CCN1 expression increases after SARS-CoV-2 infection in cells and tissues outside the brain. These findings suggested that ACE2 and CCN1 may be involved in the pathogenicity of SARS-CoV-2.
Additionally, we succeeded for the first time in confirming the expression of ACE2 and CCN1 at single-cell resolution in neural stem/progenitor cells and neurons differentiated from human iPS cells, demonstrating the utility of experimental systems using these neural cells for COVID-19 research.
Furthermore, through RNA sequencing of human iPS cell-derived neural stem/progenitor cells, we revealed that the γ-secretase inhibitors compound 34 and DAPT have the effect of suppressing the expression of CCN1, which is considered a pathogenic regulatory factor.
These research findings suggest that suppressing CCN1 expression may alleviate damage to the central nervous system caused by COVID-19, and are expected to lead to progress in elucidating the exacerbation mechanism of COVID-19-related central nervous system disorders and in developing therapeutic drugs.
This research was published in "Inflammation and Regeneration" on September 11, 2020 (UK time).
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