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.

Upregulating Human Cathelicidin Antimicrobial Peptide LL-37 Expression May Prevent Severe COVID-19 Inflammatory Responses and Reduce Microthrombosis

“…Another preprint study analyzing infection by SARS-CoV-2 in macaques found the formation of Lewy bodies ( 138 ). These plaques, which are predominantly composed of alpha-synuclein, are associated with the pathology of Parkinson’s disease and have been hypothesized to derive from a viral etiology including influenza A, norovirus and others ( 139 – 141 ). In a preprint, data from autopsies corroborated the presence of SARS-CoV-2 in all lobes of the brains of COVID-19 patients although there was a lack of inflammation ( 142 ).…”

Can SARS-CoV-2 Infection Lead to Neurodegeneration and Parkinson’s Disease?

“…Molecular investigations have established links between COVID-19 and PD focusing on protein interactions. In all, 44 proteins in the CNS implicated in PD were found to interact with 24 host proteins from the lung that interact with SARS-CoV-2 viral proteins [ 106 ]. The two most promising interaction candidates were Rab7a and NUP62 [ 106 ].…”

“…In all, 44 proteins in the CNS implicated in PD were found to interact with 24 host proteins from the lung that interact with SARS-CoV-2 viral proteins [ 106 ]. The two most promising interaction candidates were Rab7a and NUP62 [ 106 ]. Rab7a is a lysosomal protein reducing the proportion of cells with α-synuclein particles as well as the toxicity of α-synuclein, whereas NUP62 is involved in autophagosome formation [ 106 ].…”

“…The two most promising interaction candidates were Rab7a and NUP62 [ 106 ]. Rab7a is a lysosomal protein reducing the proportion of cells with α-synuclein particles as well as the toxicity of α-synuclein, whereas NUP62 is involved in autophagosome formation [ 106 ]. The comparison of transcriptomic modulations induced by SARS-CoV-2 and PD also revealed significant overlap in several pathways [ 107 ].…”

Impact of SARS-CoV-2 on Host Factors Involved in Mental Disorders

“…Additionally, the lack of detected viral gene expression in the CNS casts doubt on the hypothesis that the cytokine storm is causing or leading contributor to the neurological damage and neuropsychiatric symptoms seen in some SARS-CoV-2 cases. Exosomes have been previously reported to aid in viral pathogenesis ( Estrada, 2021 ).…”