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.

New‑onset non‑motor symptoms in patients with Parkinson's disease and post‑COVID‑19 syndrome: A prospective cross‑sectional study

“…There are several potential mechanisms underlying the aggravation of PD-related neurodegeneration due to SARS-CoV-2 as follows: i) The poor absorption of anti-parkinsonian medications due to drug interaction with cough suppressants for SARS-CoV-2( 10 ); ii) SARS-CoV-2 neurotropism of particularly vulnerable substantia nigra involved in the onset and progression of PD in vitro and human post-mortem studies ( 11 , 12 ); iii) enhanced neurodegeneration due to the persisting neuroinflammation process; SARS-CoV-2-related exosomes, in particular, have the potential to transmit SARS-CoV-2 fragments, transcriptional factors, and inflammatory mediators to brain cells, resulting in prolonged neuroinflammation and α-synuclein aggregation, which may lead to the worsening of PD symptoms. α-synuclein can enhance the SARS-CoV-2-mediated activation of microglia and the NLR family pyrin domain containing 3 inflammasome via the angiotensin converting enzyme 2/NF-κB pathway ( 13 , 14 ). Dopamine or inflammatory marker levels were not assessed in the present study; however, the authors aim to examine these in future studies.…”

Controversial Properties of Amyloidogenic Proteins and Peptides: New Data in the COVID Era

“…An interesting hypothesis is that SARS-CoV-2 proteins are carried out as exosomal cargo together with host proteins, promoting neurodegenerative and neuroinflammatory cascades, leading to the development of synucleinopathies [ 86 ].…”

Intrinsic factors behind long‐COVID: I. Prevalence of the extracellular vesicles

“…These commonalities may be represented in exosomal cargo that is altered by the virus in connection to the severity of the sickness. The SARS‐CoV‐2‐related exosomal cargo moves from the periphery to the brain and carries SARS‐CoV‐2 RNA, viral proteins, inflammatory mediators, and modified host proteins that may act as promoters of neurodegenerative and neuroinflammatory cascades and eventually result in the development of parkinsonism 81 …”

“…The SARS-CoV-2-related exosomal cargo moves from the periphery to the brain and carries SARS-CoV-2 RNA, viral proteins, inflammatory mediators, and modified host proteins that may act as promoters of neurodegenerative and neuroinflammatory cascades and eventually result in the development of parkinsonism. 81 Neuronal-enriched extracellular vesicles (nECVs) likely represent the neuron's condition in real-time. 82,83 From people with HIV-related cognitive impairment, Alzheimer's disease (AD), 84 and traumatic brain injury (TBI), 85 nECVs carrying the neurotoxic proteins amyloid beta (Aβ), neurofilament light (NFL), and/or the inflammatory protein high-mobility group box 1 (HMGB1) were identified.…”