Post-COVID-19 Parkinsonism and Parkinson's Disease Pathogenesis: The Exosomal Cargo Hypothesis

Abstract

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease after Alzheimer's disease, globally. Dopaminergic neuron degeneration in substantia nigra pars compacta and aggregation of misfolded alpha-synuclein are the PD hallmarks, accompanied by motor and non-motor symptoms. Several viruses have been linked to the appearance of a post-infection parkinsonian phenotype. Coronavirus disease 2019 (COVID-19), caused by emerging severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, has evolved from a novel pneumonia to a multifaceted syndrome with multiple clinical manifestations, among which neurological sequalae appear insidious and potentially long-lasting. Exosomes are extracellular nanovesicles bearing a complex cargo of active biomolecules and playing crucial roles in intercellular communication under pathophysiological conditions. Exosomes constitute a reliable route for misfolded protein transmission, contributing to PD pathogenesis and diagnosis. Herein, we summarize recent evidence suggesting that SARS-CoV-2 infection shares numerous clinical manifestations and inflammatory and molecular pathways with PD. We carry on hypothesizing that these similarities may be reflected in exosomal cargo modulated by the virus in correlation with disease severity. Travelling from the periphery to the brain, SARS-CoV-2-related exosomal cargo contains SARS-CoV-2 RNA, viral proteins, inflammatory mediators, and modified host proteins that could operate as promoters of neurodegenerative and neuroinflammatory cascades, potentially leading to a future parkinsonism and PD development.

Keywords: Parkinson’s disease; SARS-CoV-2; alpha-synuclein; exosomes; inflammation; neurodegeneration; neuroinflammation; parkinsonism; post-COVID-19; virus.

Figure 1

A schematic diagram of SARS-CoV-2 infection and Parkinson’s disease (PD) development overlaps listing shared clinical manifestations, common neuroinflammatory events, and mutually activated molecular pathways.

Figure 2

A hypothetical quasi-infectious model of CNS proteopathic seeding, with SARS-CoV-2 as the model virus. At step 1, SARS-CoV-2 neuroinvasion can occur either as a primary event by infecting neurons, or following infection of non-neuronal cells, such as brain endothelial cells, olfactory epithelial cells, or cells from peripheral infected tissues. Successful infection either of non-neuronal cells (2) or neurons (3) could lead to the production of exosomes that could be transmitted transynaptically (3), or intercellularly (4). The quasi-infectious concept indicates that the exosomal cargo is pathogenic and may be enhanced by the presence of viral components (5). SARS-CoV-2 S and N proteins could potentiate the formation of amyloid fibrils by endogenous α-syn in recipient cells. At the same time, exosomes could transmit α-syn to other brain cells in a “prion-like” mode. Exosomal immunomodulatory molecules could enhance neuroinflammatory processes in both neuronal and glia cells, while transcriptional regulators and miRNAs might activate intracellular signaling pathways and regulate gene transcription pertinent to neuroinflammation, oxidative stress, and other homeostatic cellular mechanisms. The ensuing microglial inflammatory phenotype turnover could enhance neuroinflammation further, resulting in enhanced neurodegeneration.