The Role of Furin in the Pathogenesis of COVID-19-Associated Neurological Disorders

Abstract

Neurological disorders have been reported in a large number of coronavirus disease 2019 (COVID-19) patients, suggesting that this disease may have long-term adverse neurological consequences. COVID-19 occurs from infection by a positive-sense single-stranded RNA virus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The membrane fusion protein of SARS-CoV-2, the spike protein, binds to its human host receptor, angiotensin-converting enzyme 2 (ACE2), to initiate membrane fusion between the virus and host cell. The spike protein of SARS-CoV-2 contains the furin protease recognition site and its cleavage enhances the infectivity of this virus. The binding of SARS-CoV-2 to the ACE2 receptor has been shown to downregulate ACE2, thereby increasing the levels of pathogenic angiotensin II (Ang II). The furin protease cleaves between the S1 subunit of the spike protein with the binding domain toward ACE2 and the S2 subunit with the transmembrane domain that anchors to the viral membrane, and this activity releases the S1 subunit into the blood circulation. The released S1 subunit of the spike protein also binds to and downregulates ACE2, in turn increasing the level of Ang II. Considering that a viral particle contains many spike protein molecules, furin-dependent cleavage would release many free S1 protein molecules, each of which can downregulate ACE2, while infection with a viral particle only affects one ACE2 molecule. Therefore, the furin-dependent release of S1 protein would dramatically amplify the ability to downregulate ACE2 and produce Ang II. We hypothesize that this amplification mechanism that the virus possesses, but not the infection per se, is the major driving force behind COVID-19-associated neurological disorders.

The Neurological Implications of COVID-19: A Comprehensive Narrative Review

“…The S1 subunit contains the receptor-binding domain RBD that interacts with ACE2, which is a membrane receptor on host cells. The S2 subunit contains the transmembrane domain (TD) and is anchored to the viral membrane [ 16 , 17 ]. Studies revealed the trimeric structure of the S protein and its conformational changes during viral attachment and entry to host cells.…”

“…A hypothesis about a novel concept states that the cleavage of the S protein S1 subunit by furin results in a higher number of free S protein molecules, even with higher affinity than the original one, that can bind other ACE2 and other receptors in various tissues. This hypothesis suggests that this mechanism is responsible for the effects of COVID-19 on the brain, and if it becomes proven, furin inhibitors and vaccines may benefit patients with neurological diseases due to COVID-19 [ 16 ].…”