Cascading from SARS-CoV-2 to Parkinson's Disease through Protein-Protein Interactions

Abstract

Background : Extensive extrapulmonary damages in a dozen of organs/systems, including the central nervous system (CNS), are reported in patients of the coronavirus disease 2019 (COVID-19). Three cases of Parkinson's disease (PD) have been reported as a direct consequence of COVID-19. In spite of the scarce data for establishing a definitive link between COVID-19 and PD some hypothesis have been proposed to explain the cases reported. They, however, do not fit well with the clinical findings reported for COVID-19 patients in general and for the PD cases reported in particular. Given the importance of this potential connection we present here a molecular-level mechanism that explain well these findings and will serve to explore the potential CNS damage in COVID-19 patients. Methods : A model explaining the cascade effects from COVID-19 to CNS is developed by using bioinformatic tools. It includes the post-translational modification of host proteins in the lungs by viral proteins, the transport of modified host proteins via exosomes out the lungs, and the disruption of protein-protein interaction in the CNS by these modified host proteins. Results : We found 44 proteins significantly expressed in the CNS which are associated with PD and whose interactions can be perturbed by 24 host proteins significantly expressed in the lungs. These 24 perturbators are found to interact with viral proteins and to form part of the cargoes of exosomes in human tissues. The joint set of perturbators and PD-vulnerable proteins form a tightly connected network with significantly more connections than expected by selecting a random cluster of proteins of similar size from the human proteome. Conclusions : The molecular-level mechanism presented here provides several routes for the cascading of effects from the lungs of COVID-19 patients to PD. In particular, the disruption of autophagy/ubiquitination processes appears as an important mechanism that triggers the generation of large amounts of exosomes containing perturbators in their cargo, which would insult several PD-vulnerable proteins, potentially triggering Parkinsonism in COVID-19 patients.

COVID-19 and Its Impact on Onset and Progression of Parkinson’s and Cognitive Dysfunction

“…However, apart from ACE2, SARS-CoV-2 can utilize neuropilin-1 (NRP1) and basigin (BSG; CD147) as docking receptors, whereas a variety of proteases such as cathepsin B and L,TMPRSS11A/B, and furin (FURIN) have been shown to promote viral cell entry as well as replication within the host cell [24][25][26]. Exposure of brain tissue to COVID-19-related injuries like hypercoagulable states, inflammation, hypoxia, immune response (cytokine storm), or dyselectrolytemia is thought to play the main role in the cerebral pathomechanism of viral damage and cause all the neurodegenerative conditions like AD and PD [27].…”

COVID-19 pandemic: A multidisciplinary perspective on the pathogenesis of a novel coronavirus from infection, immunity and pathological responses

“…(2, 6, 179), the nervous system, the urinary system (2020), and the hematological system in addition to the respiratory and immune systems (139,180). This is partly due to the widespread expression of ACE2 as a SARS-CoV-2 receptor in tissues and organs, and partly because SARS-CoV-2 causes a series of systemic pathological manifestations, such as cytokine storm and disorders of coagulation mechanisms (74,181,182).…”