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

Abstract

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 hypotheses 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 mechanistic hypothesis that explains well these findings and will serve to explore the potential CNS damage in COVID-19 patients. The 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. Our hypothesis is supported by finding 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. The molecular-level mechanistic hypothesis 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.

Keywords: COVID-19; Parkinson’s disease; exosomes; molecular mechanisms; post-translational modifications; protein–protein interactions.

Figure 1

General mechanism of lungs-to-CNS cascade giving rise to PD in COVID-19 patients. See text for explanation.

Figure 2

Protein-protein interaction network of all PD-VPs identified in this work and their perturbators. The network is built using STRING, and the edges are colored according to the way in which the corresponding PPI was determined: cyan, from curated databases; magenta, experimentally determined; green, gene neighborhood; red, gene fusions; blue, gene co-occurrence; lemon green, gene neighborhood; black, gene fusions; violet, gene co-occurrence.

Figure 3

Cascading effects from SARS-CoV-2 proteins (left) to perturbators (middle) and from them to PD-VPs (right).

Figure 4

A schematic model explaining the involvement of NUP62 and G3BP1 proteins in the development of PD due to the effects of SARS-CoV-2 (see text for explanation).